The Oncologist, Vol. 6, No. 6, 547-548,
December 2001
© 2001 AlphaMed Press
FUNDAMENTALS OF CANCER MEDICINE |
The Molecular Perspective: Antibodies
David S. Goodsell
Correspondence:
David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Website:http://www.scripps.edu/pub/goodsell
Early in the Twentieth Century, Paul Ehrlich speculated on the use of antibodies as "magic bullets" to seek out and destroy cancer cells. Antibodies, also known as immunoglobulins, are truly magical molecules. Each antibody (Fig. 1 ) binds to one specific target. Using the power and diversity of the immune system, antibodies may be created to seek out and bind to nearly any target molecule: small targets like steroids or morphine, large targets like proteins and DNA, or even molecule lipids that we don't normally associate with specific recognition. Although they have not turned out to be the comprehensive solution to cancer, antibodies have revolutionized biochemical research, medical diagnostics, and a host of other useful applications where specific molecular recognition is needed.
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Figure 1. Antibody structure. A typical antibody is composed of four separate chains: two heavy chains, colored here in yellow, and two smaller light chains, colored here in orange. Other forms may have several of these linked together into a larger complex or an added membrane-binding tail extending from the bottom. The chains associate into a flexible structure with three arms. At the center, the two heavy chains associate and link the complex together. On the remaining two arms, extending right and left here, the light chains associate with the heavy chains to form the specific binding site, which is found at the tips of the two arms. The antibody molecule is highly flexible, as seen in the twisted, unsymmetrical structure shown here. This mobility allows the antibody to accommodate to different topographies of its targets, finding two adjacent sites of binding on a bacterial or viral surface. Coordinates were taken from entry 1igt at the Protein Data Bank (http://www.pdb.org).
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Your body makes about a hundred million different types of antibodies, each made by an individual B-lymphocyte. As B-cells develop, they invent a new antibody through a modular recombination of genes. Each cell then specializes in the production of its own single type of antibody. These cells display a version of their antibody tethered to their cell membrane. If they encounter anything that sticks to it, they proliferate and within a few days begin to churn out large quantities of the soluble form of the antibody.
Antibodies in the blood are used in two major capacities. When fighting viruses, antibodies directly block binding and infection. Antibodies coat the surface of the virus, physically covering the sites that bind to cell surface receptors. The artificial antibody shown in Figure 2 performs a similar function, binding to tissue factor and acting as an anticoagulant. Secondly, antibodies act as effectors that recognize foreign molecules and mobilize defenses against them. For instance, antibodies bind to the surface of bacteria, providing a ready handle for macrophages to attach and consume the infecting cell. These functions are essential for protection of our body from foreign invaders. We make a big investment in antibodies: they comprise one-fifth of the protein in our blood serum (Fig. 3).
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Figure 2. Immunoglobin combining sites. The heart of the immunoglobulin is the specific combining site, formed by several genetically diverse loops at the tip of the light and heavy chains. In the structure shown here, only one arm of the antibody is shown, in yellow and orange, bound to tissue factor, shown in blue. This particular antibody fragment will bind tightly to tissue factor in the body, blocking its normal function in blood coagulation. In the illustration on the right, the two have been separated to show the intimate interaction. The lines show hydrogen bonds that are formed in the complex and the atoms colored green are in contact in the complex. Notice that the antibody closely matches the shape and chemical characteristics of the protein that it recognizes, forming a tight, stable fit. Coordinates were taken from entry 1ahw at the Protein Data Bank.
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Figure 3. Immunoglobulin in the blood. Blood serum is filled with antibodies, circulating and searching for foreign molecules. In this illustration, the antibodies are colored yellow: look for Y-shaped IgG, IgA with two antibodies back-to-back, and IgM with five antibodies in a star. Other molecules in this portion of blood serum include stick-like fibrinogen molecules, snaky von Willebrand factor, low density lipoproteins (large circular molecules), and many small albumin proteins.
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Both approaches are being tested for cancer treatment. Antibodies are used to block key receptors on tumor cell surfaces, compromising their function. Antibodies may also be used to recruit the cellular arm of the immune system, planting a homing beacon on the transformed cell. The remarkable specificity of antibodies is also being harnessed in other ways. As discussed in a previous installment, antibodies are being paired with powerful toxins to create specific poisoning agents that seek out cancer cells and kill them. Antibodies are also being employed for diagnosis, helping to identify the source of a tumor and the most likely course of treatment.
The difficulty, of course, is that cancer cells are derived from normal cells and often look very similar, at least immunologically. They have similar proteins displayed on their surfaces and thus may be hard to distinguish from healthy cells. In some cases, a few proteins may be changed in the process of transforming the cell, providing a ready handle for recognition. Tumors caused by chemical or radiation transformation may show these changes. In other cases, a virus may be responsible for transformation and viral proteins displayed on the cell surface may provide recognizable targets. In most cases, however, the differences are far more subtle, and tumor-binding antibodies will also bind to cells with the same lineage as the tumor cell. This will lead to side effects in treatment and false positives when antibodies are used in diagnosis.
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ADDITIONAL READING
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 Top
 Additional Reading
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Bast RC, Mills GB, Gibson S et al. Tumor immunology. In: Holland JF, Bast RC, Morton DL et al., eds. Cancer Medicine. Baltimore: Williams & Wilkins, 1997:207-242.
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Davies DR, Chacko S. Antibody structure. Acc Chem Res 1993;26:421–427.[CrossRef]
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Janeway CA. How the immune system recognizes invaders. Sci Am 1993;269:72–79.[Medline]
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