molecule (yr)
3.2 Clinical Characteristics of Biologic Drugs
3.2.1 Biologics vs. Small Molecule Drugs
The unique manufacturing, intellectual property protection, and market potential of biologic drugs has been described previously in this chapter. The remainder of this chapter will review why biologics are gaining a more prominent place in medicine, and what characteristics they possess that small molecule drugs do not or cannot. Small molecule drugs currently make up more than 90% of pharmaceutical therapeutics used for treating disease.11 They are relatively easy to develop and suit their intended purposes reasonably well; a small molecule can be an effective enzyme inhibitor or receptor ligand, for example. However, there are noteworthy clinical limitations with this therapeutic approach. Typically, for a small molecule to be effective, it needs to be enveloped or be reasonably close to its target protein or transporter; the better the fit, the stronger the affinity and this often relates to how significant the drug's impact is on the human body. Small molecules bind to receptors in similar fashion and when doing so they compete with the natural ligand, which results in agonist, antagonist, or partial agonist/antagonist activity. Most cellular functions in the body, however, are mediated by proteins interacting with other proteins.11
A major limitation of traditional small molecule drugs is that they simply fit into a specific destination that results in a biological perturbation, but do not necessarily receive feedback from the body after the drug change has taken place. This can be helpful for inhibiting a bacterial infection or other processes that require one‐directional activity, but it can result in unpredictability for more complex biological processes. For example, a small molecule beta‐blocker such as propranolol will continue blocking beta‐adrenergic receptors regardless of whether a patient is sitting, standing, or exercising. Another issue is that small molecule chemicals are not always site‐specific and off‐target systems can be affected. Nonselective beta‐blockers are contraindicated in some asthmatic patients for this reason; in addition to relaxing smooth muscle in the heart, they can also affect beta receptors in the lung resulting in bronchoconstriction.
Conversely, as biologic drugs can mimic normally existing (endogenous) proteins or protein interactions, they can receive feedback from biological systems in the body while producing their therapeutic activity. Biologic drugs can act more specifically and are often far more potent than small molecules. They more closely resemble naturally occurring proteins within the body and can be more effective in treating diseases. How closely a biologic drug resembles human proteins can have significant impact to its safety and efficacy. Biopharmaceuticals can generally be described by three major areas of their use2:
Prophylactic/ preventive use such as vaccines
Therapeutic use such as antibodies or enzymes
Replacement use such as with growth factors or hormones
3.2.2 Vaccines
Vaccines were the first biologic drugs to be developed and regulated by the FDA (Table 3.4). National and global viral pandemics have continued to push research scientists to develop new vaccines throughout the 1900s
Table 3.4 A history of vaccine development and regulation in the United States.
Source: Bren.12
| Polio vaccine |
| In 1938, former US President Franklin D. Roosevelt began a “War on Polio” with the creation of the National Foundation for Infantile Paralysis. In 1954, Jonas Salk's inactivated polio vaccine was tested in 1.8 million children. In 1955, all polio vaccinations were suspended due to ineffective batches of the vaccine circulating in the market and would not resume until all manufacturing facilities were inspected and reviewed to ensure procedures for safety testing were in place. |
| German measles vaccine |
| A global epidemic of German measles (rubella) spread to the United States in 1964, infecting about 12.5 million people that year. Rubella is typically a mild virus affecting children and young adults, but it can also pass to an unborn child if pregnant women are infected, resulting in conditions such as mental retardation, blindness, deafness, and heart defects. In 1966, two former Center for Biologics Evaluation and Research (CBER) directors developed the first experimental vaccine, and in 1969, the first vaccines were marketed. By 1988, there were only 225 reported cases of rubella in the United States. |
| Influenza vaccine |
| It is estimated that the influenza pandemic of 1918 caused 20 million deaths worldwide. In the 1940s, scientists at the Division of Biological Control – a CBER predecessor – developed the first reliable potency test for flu vaccine so that manufacturers could produce uniform products with desired effectiveness. In 1945, the first flu vaccine was developed, and today CBER works with manufacturers on an annual basis to assist in development and production of annual updated vaccines to keep responding to the ever‐evolving influenza virus. |
3.2.3 Antibodies
Antibodies are immunoglobulins, i.e. proteins with immune functions. Immunoglobulins are categorized into five classes, which identify their structural makeup and the types of immune responses produced: immunoglobulin G (IgG), IgD, IgA, IgM, and IgE. IgG is the most common immunoglobulin in the body, whereas IgE makes up less than 1%.2 The human body produces antibodies via B cells to attack and destroy antigens. Antigens are foreign substances that the body identifies as invasive and requiring removal. In individuals with autoimmune diseases, such as rheumatoid arthritis or lupus, the body incorrectly identifies itself as being foreign and will attack its own cells. Augmenting this misaligned process can produce clinical benefit and is a target for biological drugs.2
There are two predominant ways to classify antibodies based on their source and how they are harvested: polyclonal antibodies and mAbs. As the name suggests, polyclonal antibodies contain many (‐poly) antibodies; not only the desired antibody to be used for a clinical effect, but also unwanted antibodies that the immune system may see as foreign. Polyclonal antibodies can be derived from horse blood samples (botulism antitoxin, diphtheria antitoxin, tetanus antitoxin), or from human donors (hepatitis A and B immunoglobulins, or immunoglobulin for measles, rabies, and tetanus, respectively).2
In this process, an antigen (foreign matter) is injected in an animal, then the animal develops an immune response mediated by B cells and produces antibodies. The antibodies are harvested and packaged for later clinical use in humans. This type of antibody development has been in existence for decades, but not without its problems. In 1901, a batch of the diphtheria antitoxin became infected with tetanus resulting in the death of 13 children. Subsequently, in 1902, the United States passed The Biologic Control act, which was meant to ensure the safety of biologics and was the predecessor of the FDA's Center for Biologics Evaluation and Research (CBER), which
