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"Fossil Record" of the Human Immune System Reveals Antibodies that Block Cancer Metastasis

Humans May Fight Battles With Cancer Every Day

La Jolla, CA, December 2, 2004—A team of researchers at The Scripps Research Institute has reconstructed the "fossil record" of the immune systems of a group of human cancer patients to investigate if they had ever produced antibodies against their disease.

The fossil record was constructed out of a "combinatorial" library of all the antibodies that were present in the blood of 20 cancer patients, 5 of whom had breast cancer. (See the description of combinatorial antibody libraries below).

Just as a paleontologist's fossil record suggests interactions of plants and animals that inhabited earth millions of years ago, the fossil record of a cancer patient's immune system may provide a glimpse of how people's immune system interacts with pathogens and cancerous tumors today.

What the fossil record shows is that the human body is capable of making numerous antibodies that have the ability to recognize metastatic breast cancer tumors.

The Scripps Research team found several antibodies within the library constructed from the cancer patients that target a surface protein, which breast cancer cells use to metastasize. Significantly, two of the antibodies they found had evolved quite sophisticated targeting mechanisms.

When tested in mouse models, both of these anti-tumor antibodies blocked the ability of human breast cancer cells to metastasize and they helped to extinguish breast cancer that had already spread.  This finding is highly significant because of the potential for using such antibodies as a new way to treat cancer. Despite recent progress in cancer therapy, no treatment is known today that prevents cancer spreading. Antibodies have been used to treat a number of human diseases ranging from rheumatoid arthritis to leukemia. The U.S. Food and Drug Administration has approved a dozen antibodies as therapeutics, and many more are under development. The work of the Scripps Research team gives hope that antibodies that were originally produced by cancer patients may help to block cancer spreading and interfere with already existing metastatic disease.

Moreover, the disease-fighting ability of antibodies taken from patients with cancer suggests that the immune system has a natural defense mechanism against cancer cells and perhaps can even maintain an active "immune surveillance" against cancer cells.

"People have talked about immune surveillance for 40 years," says Scripps Research President Richard A. Lerner, who is Lita Annenberg Hazen Professor of Immunochemistry, Cecil H. and Ida M. Green Chair in Chemistry, and an investigator in The Skaggs Institute for Chemical Biology at The Scripps Research Institute. "The fossil record suggests that we fight cancer every day."

Scripps Research Associate Professor Brunhilde Felding-Habermann, who led the research adds, "It is possible that many of us, at some point in time, have malignant cells in our body, but that we don't notice them because the immune system eliminates them before they can establish symptomatic cancer".  

Several other Scripps Research investigators were involved in the research, which is being published in an upcoming issue of the journal Proceedings of the National Academy of Sciences. This includes Kim D. Janda, who is the Eli R. Callaway Professor of Chemistry and an investigator in the Skaggs Institute for Chemical Biology at The Scripps Research Institute. Janda and his group Antonietta Lillo, Shufei Zhuang, Changshou Gao, and Shenlan Mao were responsible for conceptualizing and preparing the cancer patient-derived antibody library. Janda and his team also mined their library and identified the antibodies found to block breast cancer metastasis reported in the paper.

Cancer, Metastasis, and the Immune System

Cancer occurs when normal cells acquire subtle mutations within their DNA that cause them to change. Often these changes make the cancer cells resistant to normal programmed cell death, and the cells will divide over and over, forming a solid tumor. Also common to cancer cells are mutations that lead them to metastasize—a word that comes from a Latin construction meaning to change position.

Metastasis is a dangerous phenomenon in which cancer cells separate from the original tumor, move into the bloodstream or lymphatic system and anchor in a distant tissue or organ. While surgeons can remove cancerous tissue, such procedures are greatly complicated if a tumor has metastasized and established many new tumors in several other organs.

The scope of this problem can be seen in statistics from the Centers for Disease Control and Prevention (CDC), which reports that by the end of 2004, an estimated 215,990 U.S. women will have been diagnosed with new cases of invasive breast cancer. Tens of thousands of women will die of the disease this year.

Cancer cells can develop in an otherwise healthy organ. Like most cells in the body, they are constantly coming in contact with the body's immune system, which may produce antibodies against them and help to clear these cancer cells from the body.

Also called immunoglobulins, antibodies are proteins produced by immune cells that are designed to recognize a wide range of foreign pathogens and unhealthy cells, such as those in tumor masses. Antibodies target antigens—proteins, carbohydrate molecules, and other pieces of the pathogen or cancer cells. These antibodies then alert the immune system to the presence of the invaders and attract lethal "effector" immune cells.

Scientists have reasoned that the immune system may be able to successfully eradicate tumors by producing the right antibodies. To see if such antibodies could be found, Felding-Habermann, Lerner, Janda, and their colleagues took blood samples from 20 cancer patients and generated the fossil record of their antibody immune response through a technology known as combinatorial antibody libraries.

A Sophisticated, Evolved Targeting Mechanism

To find antibodies produced by cancer patients that bind selectively to the most dangerous subset of cancer cells, namely those that cause cancer spreading, the researchers created a combinatorial antibody library to select from among billions of protein variants for those that bound to a particular target. In this technique, libraries of antibodies are fused to the viral coat protein of phage—a filamentous virus that infects bacteria. Then the virus is allowed to reproduce in culture, where it makes new copies of itself and generates the antibody library.

Since the phage particles display these proteins on their surface, a scientist can select antibodies in vitro by passing the viral stew over a stationary phase containing the target substrate—in this case metastatic breast cancer cells. Since metastatic and non-metastatic breast cancer cells share so many surface molecules, the trick was to eliminate first those antibodies that react with both cell types, and then select only specific antibodies that bind exclusively to the metastatic tumor cells.

"We wound up with some antibodies that are extremely interesting," says Felding-Habermann. Several of them, she says, bound to a protein on the surface of the cancer cell called integrin aub3.

Integrins are large protein complexes made up of two different types of polypeptide chains (called the alpha and beta subunits) that come together to form a "heterodimer," which is expressed at the surface of a cell. Most of the integrin sticks out at the surface of the cell, where it binds to molecules on the outside and mediates the cells's interactions with other cells and with the surrounding extracellular matrix, to maintain the integrity of tissues.

But integrins are also implicated in cancer metastasis because they help the cancer cells that enter the bloodstream and to invade new tissues. When a cancer cell is in the circulation, it may have difficulty locking onto new tissues because of the interference of blood cells, plasma proteins, and the sheer force produced by blood flow. Cancer cells need something like a hook to anchor themselves to a particular spot under these dynamic flow conditions. Integrins can provide such hooks.

Breast cancer cells display the high-affinity form of a particular integrin on their surfaces. This integrin, called aub3, allows the tumor cells to interact with proteins in the bloodstream. Once bound, these proteins can form molecular bridges between the tumor cells and blood platelets, and the tumor cells can use these bridges to attach to new tissues where they can establish new tumors.

However, if antibodies such as those discovered by the Scripps Research scientists are present, they may block this process.

"Cancer patients can produce antibodies that may very actively interfere with metastasis," says Felding-Habermann. One way that the antibodies can do this is by recognizing and binding to the activated form of integrin aub3, blocking the integrin from attaching to platelets and preventing the cancerous cells from arresting in the bloodstream and invading new tissues.

Significantly, two of the antibodies the scientists discovered target the active form aub3 integrin through its characteristic motif known as "RGD," which refers to the characteristic triad of amino acids arginine–glycine–aspartic acid. The finding that the discovered antibodies mimic natural ligands of integrins, but at the same time display a much greater specificity, is a remarkable example of convergent evolution: Humans and other mammals evolved the aub3 integrin binding motif over millions of years of evolution, and the antibodies reached the same motif through a much faster evolution—in mere years or less. This demonstrates the power of the immune system to evolve a best-fit solution over the lifetime of an individual.

The research article, "Combinatorial antibody libraries from cancer patients yield ligand mimetic RGD cointaining immunoglobins that inhibit breast cancer metastasis" is authored by Brunhilde Felding-Habermann, Richard A. Lerner, Antonietta Lillo, Shufei Zhuang, Martin R. Weber, Sandra Arrues, Changshou Gao, Shenlan Mao, Alan Saven, and Kim D. Janda and is available online at: http://www.pnas.org/. The article will be published in the December 7, 2004 issue of the journal Proceedings of the National Academy of Sciences.

This work was supported by funds from the National Institutes of Health, the U.S. Army Breast Cancer Research Program, the Skaggs Institute for Research, and the Stein Endowment Fund.

About The Scripps Research Institute

The Scripps Research Institute in La Jolla, California, is one of the world's largest, private, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases and synthetic vaccine development.

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lung 
Metastatic foci of fluorescent human breast cancer cells that had developed in the lungs of immune deficient mice. The number and size of metastases found in animals treated with breast cancer patient derived antibody were much reduced (lower image) compared to animals treated with ineffective control antibody (upper image).

 

fossil 
Convergent evolution of critical sequences in ligand-mimetic antibodies and natural ligands causes both to target the same receptor protein (Artwork by Dr. Art Olson)