Monoclonal Antibodies.

Monoclonal antibodies were invented in 1978 in a laboratory in Cambridge, England. The immense importance of that accomplishment was not comprehended at the time for, like many revolutionary scientific events, it was considered to be largely a curious achievement of interest only to specialized scientists.

At present the potential for monoclonal antibodies in many fields of human endeavor, not only in medicine but also in a wide range of industrial and academic pursuits, has made them one of the most active areas of research. The commercial prospects alone may reach billions of dollars. In fact, one British observer has noted that the general concept of a monoclonal antibody was not patented by its discoverers, yet the potential value may exceed that of North Sea oil. The benefit to mankind from medical uses could be extraordinary, and early results have done nothing to restrain this enthusiasm.
A monoclonal antibody is a highly specific antibody produced by a special kind of man-made hybrid cell called a hybridoma, which makes the antibody in greatly increased quantity. In contrast, the antibodies with which most of us are familiar in their role of defending us against allergens and other disease-causing organisms are manufactured by a family of several antibody-producing cells in relatively minuscule amounts and are not truly specific or uniform in their biological properties.
Normally when a human being is exposed to a substance the body recognizes as "foreign" or different from its own tissues and chemicals, several protective systems attempt to neutralize, weaken, and dispose of the invading substance. For example, the body may react through its various metabolic processes to alter the chemical structure of the foreign substance. Both the kidney and liver contain a wide range of enzymes that react with foreign substances, including drugs, metabolizing them into substances that are either used by the body or excreted. The immune system also deals with foreign substances, particularly bacteria and viruses.
The human immune system operates in several ways. Cellular immunity works through specialized cells that directly attack foreign invaders. Humoral immunity works through cells that make compounds to attack and neutralize foreign proteins. The complex molecules we know as antibodies were the first of these substances to be recognized. Antibodies are produced by plasma cells, a line of cells found principally in the bone marrow, lymph nodes, and spleen. The answers to the crucial questions of how these cells "know" when a foreign substance is present and which antibody to make in order to neutralize it are complex and just becoming clear to researchers in immunology.
In a sense, however, there are certain pivotal steps to the process that are not very precise. In fact, the plasma cells respond by making many different kinds of antibodies to a foreign protein, some of which may work well in neutralizing it while others work poorly or not at all. This range of effect or lack of it occurs because foreign proteins are generally very large molecules, and while some antibodies may be highly effective because they are strongly directed against a vital part of the foreign protein's molecular structure, others may be ineffective because they are weak or directed against an unimportant part. The creation of monoclonal antibodies was a significant achievement because it created a method for the continuous production in the laboratory of a single antibody selected specifically for its unique properties.

This is the way it works: Normal animals, usually a purebred strain of mice, are exposed to the foreign protein to which antibodies are desired. The plasma cells in the mouse's spleen are stimulated to react, producing a wide range of antibodies, both effective and ineffective. The mouse's spleen is removed and its plasma cells are separated out. They are then fused by a variety of processes with a cancerous plasma cell, called a plasmacytoma, producing the hybridoma. The cancerous plasma cells are taken from a mouse with multiple myeloma, a malignancy of plasma cells that is similar to the human disease with the same name. These cells have many of the general properties of cancer cells, including uncontrolled rapid growth and disordered metabolic processes. They also produce a single antibody in greatly increased amounts, hundreds or thousands of times more than is required by a normal system. With luck, the hybridoma that results from fusing a single "immortal" plasmacytoma cell with a normal cell will have the desired properties of each parent cell. It will produce a single highly specific antibody in great amounts and be stable, meaning the cell line will not die out or gradually reduce its level of antibody production. In practice, many thousands of hybrids are produced and are then screened to select the ones with the desired properties.

Present laboratory methods permit the selection and culturing of animal cells that are descended from a single cell by a consecutive series of cell divisions a process known as cloning. A monoclonal antibody is the unique molecule derived from a single clone. Conventional antibodies, in contrast, are generally a collection of several types of antibody molecules and are called polyclonal.
Medical researchers and clinicians are now using monoclonal antibodies to improve the diagnostic accuracy of many laboratory tests that previously were based on conventional antibodies. More importantly, monoclonal antibodies are being used for new diagnostic tests, with a goal of finding new ways to diagnose and treat cancer.

Cancer researchers have long searched for markers substances found in the blood or urine that are secreted by a cancer and indicate its presence or degree of activity. Such markers, if they exist, could be used to evaluate the effectiveness of treatment and also in follow-up monitoring after treatment. An increasing concentration of the markers might indicate a relapse or regrowth of cancer cells, possibly long before the onset of new symptoms. In addition, tests for markers might be used to screen otherwise apparently healthy people for cancer.

At present only the monitoring function can be performed by using antibodies against carcinoembryonic antigen (CEA) and alphafetoprotein (AFP), two substances that are secreted into the blood stream by tumors of the colon and liver respectively. Tests for these substances, based on conventional polyclonal antibodies, use indicators to show whether the antibodies have reacted with the substance in question. Monoclonal antibodies can and are being used to improve the accuracy of these and other tests.

The discovery of oncogenes, the atypical genes that are being found in association with several common types of human cancer (breast, lung, bladder and others), may increase our basic understanding of the processes that lead to the malignant transformation in normal cells. The mechanism by which oncogenes control the transformation process is being intensively studied. Evidence to date indicates that the abnormal oncogene is formed by mutation or by transfer from a virus. The abnormal gene, which may differ from a normal one in only a very small part of its structure, results in the synthesis of either an abnormal protein or enzyme. This substance, which may actually occur under normal conditions but is now produced in inappropriately high or low amounts, influences the control of cellular metabolism and reproduction, giving the cell the characteristics of a malignant growth. The final result, which may in fact require the combined effects of two different oncogenes, is a cancer cell capable of growing abnormally and invading other tissue.

Researchers have identified approximately twenty human oncogenes, which fall into three main groups. The abnormal protein manufactured under the direction of the oncogene can be identified and synthesized in a laboratory, and monoclonal antibodies can then be made against these substances or used to search for them in blood and urine. Researchers hope that the sensitivity and accuracy of monoclonal reaction may make them a promising tool in finding cancer markers.