Although the term biotechnology was first used in 1917 in reference to new agricultural technology, it is currently applied to the use of molecular biology to produce drugs or diagnostics (generally proteins) previously unobtainable in pure form or in sufficient quantities.1 The US Pharmacopeia states that the current success of biotechnology is due mainly to 2 major scientific advances: the development of recombinant DNA technology, allowing genes of 1 species to be transplanted into another species; and the development of techniques for making large quantities of monoclonal antibodies. Other technologies?such as transgenic animals and plants, gene therapy, and anti-sense DNA?also may prove to be important in the future.2 A recent computer search of the 2002 issues of the weekly newsmag-azine Chemical and Engineering News for the keyword biotechnology identified more than 200 articles and news items. This example shows how hot the biotechnology (biotech) field is at present.
To update the practicing pharmacist?s knowledge about this exciting field, this article reviews the 2 processes by which biopharmaceuticals are made at present, some problems connected with their use, and the pharmacist?s role in the care of patients receiving biotech drugs.
Manufacture of Biotechnology Drug Products
Recombinant DNA (rDNA)
The major steps in the production of a desired protein are as follows:
1. Identification of the protein to be produced
2. Isolation of the gene that codes for the protein
3. Insertion of the gene into a suitable vector (carrier; eg, a plasmid)
4. Insertion of the vector into a host cell
5. Isolation of clones of the transformed cell line that produce adequate amounts of the protein
6. Preservation of the above cells
7. Scale-up of the cloned cells in a fermentation or cell-culture process to yield the protein product2
The earliest biotech products used Escherichia coli as the host cell (step 4 above), because the molecular biology of that bacterium was well understood. Now yeast or mammalian cells, particularly Chinese hamster ovary cells, are generally employed.
Monoclonal Antibodies (MAB)
Antibodies are proteins produced by differentiated B lymphocyte cells. To obtain an antibody that recognizes a single antigen and has an unvarying binding constant, it is necessary to clone a single B cell. Because B lymphocytes have a limited life span in culture, they must be "immortalized" to enable ongoing production of mon-oclonal antibodies. This is done by chemically induced fusion with a mouse myeloma cell. The resulting cell, called a hybridoma, inherits from the B cell its antibody-producing ability, and from the mouse cell the ability to reproduce indefinitely. For therapeutic or diagnostic applications, MABs are coupled with another substance, such as an oncolytic or a radionuclide. The conjugate is then directed to a specific target by the antibody moiety. Monoclonal antibodies are produced in quantity by growing the hybridoma in vitro (cell culture) or in vivo (eg, culturing in mice and collecting ascites fluid). The Table gives some basic information on selected therapeutic products that apply rDNA or MAB technology. Biotech medicine continues to produce exciting developments, as exemplified by recent clinical reports on new MABs. Omalizumab is directed against the receptor-binding domain of the circulating immunoglobulin IgE. It prevents IgE from attaching to mast cells and setting off the cascade that results in allergic signs and symptoms. This truly novel approach to the treatment of allergic diseases has been reviewed by the FDA, which requested additional data. The manufacturer planned to submit the data in the 4th quarter of 2002, which should bring final FDA action in the first half of 2003.3
A pair of clinical reports have recently appeared on natalizumab, an antagonist of alpha 4 integrin, classed as a selective adhesion molecule inhibitor. This antibody shows promise in the treatment of 2 unrelated chronic diseases: multiple sclerosis and Crohn?s disease.4,5
Problems and Challenges
No new therapy is problem-free, and biopharmaceuticals have their share of problems. The manufacturing processes, as outlined above, are a complex and difficult procedure, requiring extensive validation and controls. The costs of development and clinical testing also must be added in, and thus the high prices of biotech products are not surprising. Xigris, recently approved for sepsis, costs an astounding $10,000 per dose. Anakinra and Enbrel, for rheumatoid arthritis, cost $15,000 to $16,000 for a year?s treatment.6 The complicated manufacturing processes also lead to supply problems. The interferon-based multiple sclerosis products suffered from shortages when they were first marketed. More than 40,000 patients have been on a waiting list with unfilled prescriptions for Enbrel, the antiarthritis drug. Its manufacturer has contracted out manufacture and has recently validated a new plant to increase supplies.7,8 Another commercial challenge is the fact that 10 major biotech drugs face patent expiration by 2005. Although there is no regulatory provision for generic applications for biotechs, the generic industry as well as third-party payers can be expected to make every effort to open this field to generic competition. The fact that some contract biotech manufacturers have excess, unused capacity will add to the pressure.9 Medically, there are certain problems over and above the adverse side effects that accompany all active medicinals. Because biotech products are proteins, the body may produce antibodies against them. The multiple sclerosis drug Avonex produced neutralizing antibodies in 24% of the patients in a clinical trial, potentially reducing the drug?s activity.10 Even biotech insulin, which is identical to human insulin, occasionally produces an allergic reaction.11 More threateningly, antibodies may be produced that not only neutralize the biotech drug, but also attack the body?s own version of the injected protein. Eprex (erythropoietin), in use in Europe for more than 10 years in patients with kidney disease and cancer, recently was discontinued because the immune system in some patients attacked and destroyed its own red blood cells. These patients now need lifelong transfusions to stay alive. Understandably, this event has sent chills through the entire biotech industry.12
The Pharmacist?s Role
In caring for patients receiving biotech medicinals, the role of the pharmacist depends largely on the treatment setting. Treatment settings vary widely. Human insulin products (eg, Humulin) are OTC products and are injected by the patient. Tissue plas-minogen activators (eg, Activase) and activated protein C (eg, Xigris) are emergency medications and thus are stocked and dispensed only by hospital pharmacists. The interferon-based multiple sclerosis products are available by prescription only, but they are injected by the patient or a caregiver. Rheumatoid arthritis patients on Enbrel may inject themselves twice weekly after proper training.
For biotech products prescribed for ambulatory patients, the community pharmacist is responsible for proper storage, dispensing, and patient counseling. Having the patient sign a waiver of counseling is especially reprehensible when biotech drugs are involved. Counseling is important in 2 areas: injection technique and side-effect monitoring. The pharmacist should study the specific injection procedure, as given in the product labeling or in the Physicians? Desk Reference,10 and should reinforce the instructions the patient may have been given by the doctor or nurse. At each renewal of the prescription, the pharmacist should question the patient about any local or systemic adverse events. Such follow-up may provide early warning of loss of drug effectiveness or serious immune system reactions. Looking at the injection site also is desirable, although most pharmacies do not provide the necessary privacy for examination of any injection site other than the arms.
Biotechnology has already enriched the medical armamentarium with products based on recombinant DNA and monoclonal antibodies, and intensive research is progressing on many more such products. Recombinant DNA technology makes various proteins secreted by the body available in sufficient quantities for therapeutic use. Monoclonal antibody technology produces antibodies engineered to attack cell receptors associated with various diseases. Although community pharmacists encounter these products only occasionally at present, they can render an important service to patients by helping them with injection technique and monitoring for adverse events. Pharmacists must keep abreast of new developments in this rapidly growing field so that, when called on, they can provide impartial and authoritative information.
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