Magnetic Attraction: Towards A New Era In Treating Rh-Factor Incompatibility

April 01, 1997

Philadelphia, Pa. -- Physicians have known for decades that fetuses positive for a red blood cell antigen called Rh-factor D are at risk when their mothers are negative for the factor. If blood from the developing fetus mingles with the mother's blood, the mother will generate powerful antibodies capable of devastating attacks on the baby's red blood cells.

Since the early 1960s, however, Rh immune globulin -- which can only be derived from Rh-negative individuals who have been exposed to Rh-positive blood -- has been given prophylactically to Rh-negative pregnant women. Rh immune globulin is itself composed of anti-Rh antibodies, yet when administered as a drug it prevents formation of the deadly antibodies against the fetus. This treatment has been very successful, but it has given rise to a new problem: As time passes, the available pool of Rh immune globulin donors exposed to Rh-positive blood prior to the 1960s dwindles. It is unethical to create new donors through intentional exposure, and no animal is able to generate the needed antibodies.

Now, Donald L. Siegel, MD, PhD, an assistant professor of pathology and laboratory medicine, has developed a new technology that promises to address this need and that may have uses against cancer and other diseases, too.

Siegel's approach extends a technique for producing large libraries of antibodies called phage display, in which molecular biologists engineer millions of bacteria to display a wide range of antibodies on their surfaces. Purified antigen -- the entity against which an antibody reacts -- is then attached to an inert laboratory surface to which the phage-displayed antibodies are exposed. The specific desired antibodies bind to the antigen and are thus isolated. This selection process, called panning, is repeated to achieve greater purity.

"The limitation, however, is that there are many important antigens -- Rh factors, for example -- that we want antibodies against but that are bound in the membranes of cells and cannot be purified in a way that maintains their native properties," Siegel notes.

To circumvent this difficulty, Siegel uses whole cells in a modified panning process. He first coats a small number of Rh-positive cells with magnetic beads and then adds a much larger number of Rh-negative cells. To this mix, he introduces a phage library developed from an Rh immune globulin donor. Most of the antibodies, against antigens of no current interest, bind to the excess of Rh-negative cells, and the desired anti-Rh antibodies bind to the Rh-positive cells. Siegel then uses a magnet to pull the target cells with their antibodies in tow away from the other cells. As with ordinary panning, repetition leads to refinement.

With this strategy, Siegel isolated more than 50 different anti-Rh antibodies in one experiment, an unprecedented number. In addition to its effectiveness, the process is inexpensive and fast. Also, differences between cells within an individual could be exploited in this way to discover diagnostic or therapeutic antibodies, such as antibodies that might act against lung tumor cells but not against normal lung cells.

-- Dr. Donald L. Siegel can be reached at (215) 662-3942.

The University of Pennsylvania Medical Center's sponsored research ranks fifth in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation -- $149 million in federal fiscal year 1996. In addition, for the second consecutive year, the institution posted the highest growth rate in its research activity -- 9.1 percent -- of the top ten U.S. academic medical centers during the same period. Penn news releases are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science, and to the SciNews-MedNews section of the Journalism Forum, a component of CompuServe. Additionally, they are distributed via the electronic news service Quadnet.

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University of Pennsylvania School of Medicine

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