What are biopharmaceuticals?

History of Biopharmaceuticals

Drugs have been used by humans for thousands of years. More than three thousand years ago, the Sumerians were the first culture to compile written medical information that outlined symptoms and treatments for disease. Most ancient cultures used medicines derived from plants and animals. These drugs were different from modern biopharmaceuticals in many ways, but the most significant difference is that the drugs were not engineered to treat a particular disease. Since there was no real understanding of the underlying problem, a rational approach to drug selection and design was difficult, if not impossible. One philosophy of medicine that developed to address this problem was called the doctrine of similitudes, in which treatments were based on similarities of structure with disease manifestation. For example, the leaves of St. John’s wort looked similar to damaged skin, so it was thought this plant extract could effectively treat cuts and burns.

It was not until the twentieth century that the underlying genetic basis for disease was discovered. The discovery that DNA is the genetic material that provides instructions to make proteins was revolutionary. In the mid-1900s, sickle-cell disease
was shown to be caused by a single nucleotide mutation from an A (adenine) to a T (thymine) in the hemoglobin beta-chain gene. This small change alters the shape of a red blood cell from a biconcave disc to a sharply pointed crescent. Although it was now possible to identify genetic mutations, there was still no way to manipulate or make changes to genetic information.

The advent of recombinant DNA
technology in the 1970s provided the first chance to engineer, or manipulate, genes. Restriction enzymes
became an important tool in this new technology. Restriction enzymes were first found in bacteria, where they function to protect the cell from foreign DNA by cutting it up at specific sequences. These sequences are usually palindromes of the letters that signify the four nucleotides that make up DNA: guanine (G), adenine (A), thymine (T), and cytosine (C). Most restriction enzymes cut the DNA in such a way that an overhang, called a sticky end, is created. Since excess unbound DNA, provided by the scientist, will readily bind its complementary base, these engineered sticky ends can be used to splice different pieces of DNA together in a laboratory. The resulting sequence is called recombinant DNA.

With the ability to engineer DNA now possible with restriction-enzyme technology, scientists looked again to use bacteria as a host “factory” in order to convert known DNA sequences into protein. Bacteria are ideal for protein production because they reproduce quickly, are easy to genetically manipulate, and can be grown in large quantities. Many bacteria contain circular pieces of DNA that are separate from their genome, called plasmids. Plasmids can be readily transferred between bacteria and are also inherited by daughter cells when a bacterium divides. With the use of restriction enzymes, plasmids are isolated from bacteria and engineered to contain a foreign gene. The recombinant plasmid is reinserted back into bacteria, which work nonstop to transcribe and translate the recombinant gene. The gene is then expressed as a fully functional protein. The first biopharmaceutical produced in bacteria was recombinant human insulin, which was marketed in 1982.

The future for biopharmaceuticals looks bright. In 1991, there were only fourteen biopharmaceuticals approved for use by the US Food and Drug Administration (FDA). By 2014, approximately 375 had been approved for use in the United States, and more than 580 major US companies were working to produce and develop biopharmaceuticals.

Design of Biopharmaceuticals

A popular method for the identification of disease-related genes is called genomics. Gene chip analysis is used to screen thousands of genes in a single experiment. This approach is drastically faster and more efficient than traditional methods and can be used for any disease, even those that are not hereditary.

Once the genomic information is obtained, it is used to build a broad understanding of how a disease gene functions and what role the gene plays in the cell. This information is gathered through the use of experimental models, genetic analysis, biochemical analysis, and structural analysis. Experimental models can range from cell culture to transgenic mice and can provide physiological information about the disease. Genetic analysis can provide information about where and when the gene is expressed. Biochemical analysis can provide information about protein-protein interactions, posttranslational modifications of the protein, and its enzymatic activity. Structural analysis can yield extremely detailed information about the physical arrangement of the atoms that make up the protein. All these approaches can identify important potential targets for treatment of the disease. A better understanding of the disease at the genetic and molecular levels facilitates the design of a biopharmaceutical.

Once a disease is better understood, it becomes possible to target a key pathway or protein for biopharmaceutical intervention. The resultant drug and the way that it is used clinically will vary from disease to disease. For example, type I diabetes
is caused by a deficiency in the hormone insulin. Without insulin, the body is not able to regulate the level of glucose in the blood. Lack of insulin was first corrected by an injection of the first biopharmaceutical, recombinant human insulin. It was developed by Genentech and marketed as Humulin by Eli Lilly & Company in 1982.

Another example of a biopharmaceutical is the enzyme tissue plasminogen activator (tPA). Most heart attacks are caused by a blood clot blocking the flow of blood through a coronary artery. Formation and removal of blood clots is a highly regulated and well-understood process. Tissue plasminogen activator is one of the key players in blood-clot removal. This knowledge led to the development of recombinant tPA, which can be provided by injection or infusion to heart attack patients. Once in the bloodstream, tPA breaks up coronary artery clots and restores blood flow to the heart, preventing any further muscle damage.

Clinical Trials

Before a biopharmaceutical can be used to treat disease, it must undergo rigorous clinical trials that test its safety and effectiveness in humans. There are four phases of clinical trials. Phase I trials involve studies on a small number of patients (fewer than one hundred) in order to determine drug safety and dosage. Phase II trials involve more patients (up to five hundred) in order to determine effectiveness and additional safety information, such as side effects. Phase III trials are the most extensive and involve large numbers of people (between one thousand and three thousand). These trials establish risk-benefit information and are compared with other currently used treatments. Phase IV trials determine the drug’s optimal use in a clinical setting.

In 2011, the entire process of drug design—from discovery to clinical trials—cost an estimated $1.5 billion and took an average of ten to fifteen years. Many years of research and millions of dollars are expended in an extraordinary effort that yields little success; only one in five thousand drugs makes it to market.

Biopharmaceuticals Today

Biopharmaceuticals are classified into several categories, including blood factors, thrombolytic agents, hormones, hematopoietic growth factors, interferons, interleukin-based products, vaccines, monoclonal antibodies, and other products. Some FDA-approved biopharmaceuticals of particular interest include Aralast, Gardasil, and ATryn. Aralast is marketed by Baxter and was approved for use by the FDA in 2003. Aralast is the trade name for the recombinant human protein known as alpha-1 proteinase inhibitor (A1PI). A1PI deficiency, also called alpha-1-antitrypsin deficiency, results in the destruction of lung tissue, which can lead to emphysema. Aralast is given to patients intravenously each week, protecting against future lung damage.

The popular vaccine Gardasil was designed to prevent genital human papillomavirus (HPV)
infection. Gardasil is marketed by Merck & Company and was approved by the FDA for use in young women in 2006. HPV is the most commonly sexually transmitted disease in the United States and has been shown to cause cervical cancer, the second leading cause of cancer deaths among women worldwide. Gardasil vaccinates against the four most common strains of HPV. It is a quadrivalent vaccine that stimulates the immune system to make antibodies that recognize and destroy HPV 6, 11, 16, and 18, protecting against future infection.

ATryn is the trade name for recombinant antithrombin III, an anticoagulant manufactured by GTC Biotherapeutics and sold by Ovation Pharmaceuticals. It is produced from the milk of transgenic goats that have been genetically modified to produce human antithrombin. In 2009, the FDA approved the use of ATryn to treat patients with hereditary antithrombin deficiency who need an anticlotting agent to undergo procedures that involve blood loss, such as surgery and childbirth. It was the first biopharmaceutical to be produced from genetically engineered animals, goats being chosen for their high reproduction rate.

A 1998 study found that more than 100,000 people in the United States die each year because of adverse drug reactions. Similarly, in 2013, the European Medicines Agency reported that adverse reactions caused approximately 197,000 deaths in the European Union annually. One trend in pharmaceutical research is the production of designer drugs through the new field of pharmacogenomics. These drugs are specifically matched to an individual patient’s genetic profile and their particular form of disease. Pharmacogenomics would make it possible to avoid adverse drug reactions. Research in pharmacogenomics will also increase the pool of drugs available to treat disease. While many drugs never make it to market because they work for only a small subset of patients, pharmacogenomic research will identify these specific patients as treatment successes.

Key Terms




clinical trial


:

an experimental research study that determines the safety and effectiveness of a medical treatment or drug




humanized antibody

:

a human antibody that has been engineered to contain a portion of a nonhuman variable region with known therapeutic activity




pharmacogenomics

:

the field of science that examines how variations in genes alter the metabolism and effectiveness of drugs





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