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SPECIAL SECTION: MONOCLONAL ANTIBODIES
WHAT ARE MONOCLONAL ANTIBODIES (MABs)? DEFINITION, DESCRIPTION, USES, HISTORY, ISSUES
Monoclonal antibodies are produced by cells that are all derived from a single antibody-producing cell. This means that they are exceptionally pure and highly specific in their action. This specificity allows them to be used in humans and in animals for disease diagnosis and treatment. MABs have had a major impact on virtually every area of investigative science and applied research.
Producing MABs requires first immunizing an animal, usually a mouse. The mouse is injected with a specific antigen--a foreign substance that the animal's immune system can recognize and respond to by producing antibodies. After the mouse’s immune system develops antibodies against the antigen, antibody producing white blood cells (B-cells) are removed from the mouse’s spleen. These cells are then fused with myeloma cells, a rapidly multiplying white blood cell cancer, to make them immortal--i.e., they will grow and divide indefinitely. A tumor of the fused cells is called a hybridoma. These cells secrete MABs.
Animals are still needed to generate the antibody-producing B-cells. No non-animal alternatives are available for this first step.
An investigator selects a hybridoma cell line that secretes a monoclonal antibody that reacts strongly with the particular protein or molecule under study. The cells must grow and multiply to form a clone that will produce the desired MAB. This is where the question of alternatives comes into play. There are two basic methods for growing these cells: injecting them into the peritoneal cavity of a mouse or using in vitro cell-culture techniques. When injected into a mouse, the hybridoma cells multiply and produce fluid (ascites) in the animal’s abdomen. This fluid contains a high concentration of antibody.
This fluid accumulation is also at the heart of the controversy concerning MAB production. Ascites fluid accumulation is known to cause discomfort and pain in human patients, and animals used in the ascites method frequently exhibit a spectrum of clinical symptoms, including: anorexia, anemia, dehydration, difficulty walking, respiratory distress, circulatory shock, and classical peritonitis.
Monoclonal antibodies were first produced in the 1970s through in vitro methods. Scientists soon discovered, however, that they could produce MABs easily and in nearly limitless supplies by using animals. Ever since, scientists, regulators and animal welfare representatives have debated such issues as: To what degree does ascites MAB production cause pain and distress? How can that pain or distress be minimized? Are there acceptable alternatives? Is there a continuing need for the ascites method?
The debates center on the method of production. Few would dispute the usefulness of monoclonal antibodies in biomedical research, diagnosis, and treatment of diseases. For example, MABs have been used to identify the normal components of the immune system and to determine if these components are under-represented (in the case of immunodeficiency diseases) or over produced (in some cancers). They have been used in therapy for many immunologically based disease processes, such as the control of tranplantation rejection. They have also been used extensively in the development of simple color tests to detect and quantify the presence of an antigen, antibody, or hormone. Commercial uses include over-the-counter pregnancy tests, which use MABs directed to protein samples in urine, as well as tests to determine glucose levels for monitoring diabetes, to detect antibiotic residues in milk, and to indicate the presence of salmonella.
The readings that follow provide a more detailed introduction to MABs and an overview of the issues involved.
University of California Center for Animal Alternatives (UCCAA) web site, section on The Mouse in Science: Monoclonal antibodies.