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NCI Researchers Develop Modified Immunotoxin for Cancer Therapy in Mouse Study

Researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), have shown in mice that just a few modifications to a shortened version of a bacterial toxin, called PE38, may be able to improve the efficacy of an immunotoxin that contains PE38 as a new therapy for cancer. As part of this new study, scientists have modified the PE38 toxin in an effort to broaden the range of the types of tumors that can be treated successfully. Immunotoxins, which are antibodies linked to toxic proteins, can selectively bind to cancer cells and kill them and immunotoxins containing PE38 have already been used as effective treatments for certain types of leukemias and lymphomas. The results appear in the December 15, 2006, issue of the Journal of Immunology*.

"Immunotoxin therapy is one of a growing number of treatments in which scientists engineer molecules to target cancer cells and leave healthy cells unharmed," said NCI Director John Niederhuber, M.D. "We have already witnessed the success of immunotoxin therapy to treat hairy cell leukemia. Now, with a roadblock to further applications apparently removed, we plan to apply this therapy to other cancers."

By using recombinant DNA techniques, scientists in the Laboratory of Molecular Biology at NCI's Center for Cancer Research (CCR) combined the PE38 bacterial toxin with portions of several different mouse antibodies. The PE38 portion was derived from a toxin secreted by a type of bacteria that kills human cells by blocking their ability to make proteins. The antibody fragments were chosen for their ability to find and bind specifically to tumor cells, thereby selectively delivering the toxin to cancer cells.

In a previous clinical trial that tested a different immunotoxin containing PE38, over half of the participants with drug-resistant hairy cell leukemia achieved complete remission after receiving at least three doses of immunotoxin. However, a related immunotoxin that also targeted solid tumors did not have similar success. Researchers discovered that in patients with solid tumors, normal immune cells quickly recognized the PE38 portion of the immunotoxin as foreign and produced antibodies against it, thereby neutralizing the therapy. In contrast, patients with leukemias, which are cancers affecting certain white blood cells of the immune system, have a diminished capacity to mount an immune response. As a result, the PE38-containing immunotoxin has enough time to target and kill cancerous cells before being attacked by the leukemia patient's immune system.

To overcome this neutralizing attack on immunotoxins when treating patients with solid tumors, the NCI researchers, led by Ira Pastan, M.D., identified the sites on the PE38 toxin that stimulate an antibody response. To do this, the scientists immunized mice with PE38 and produced 60 different types of antibodies that reacted with the immunotoxin. Collectively, these 60 antibodies reacted with only seven regions on PE38. Furthermore, these same seven regions were recognized by the immune systems of patients who made antibodies to PE38 after receiving immunotoxin treatment.

The mouse antibodies were then used to pick out exactly which amino acids within the seven responsive regions were to blame for the undesirable immune response. Using this information, the researchers were able to create seven mutant immunotoxins that no longer reacted with these antibodies, yet were still able to kill cancer cells. Studies are now underway to incorporate these seven mutations in a single immunotoxin molecule that should be less reactive with the mouse's immune system.

"Figuring out which mutations abolish antibody binding might also reveal common structural features of proteins that can elicit an immune response," said Raffit Hassan, M.D., head of the Solid Tumor Immunotherapy section and one of the study's authors. Hassan and his colleagues hope that these simple changes in PE38 will reduce a patient's chances for experiencing an immune response to PE38, allowing the immunotoxin to be effective against solid tumors.

"We are currently testing to see whether these modifications to the PE38 toxin can reduce the immune response in mice. If we can diminish the immune response to this therapeutic molecule, we will expand its use to include a wider range of human cancers, such as ovarian cancer," said Pastan.

A diagram of the molecular process involved in this research follows:

The BL22 immunotoxin combines a genetically engineered bacterial toxin with an antibody (anti-CD22) that recognizes and binds to CD22 protein.  CD22 is present at high levels on the surface of many kinds of leukemia cells. Art by Jeanne Kelly.

For more information on Dr. Pastan’s research, go to http://ccr.cancer.gov/staff/staff.asp?profileid=5782.

For more information on Dr. Hassan’s research, go to http://ccr.cancer.gov/Staff/Staff.asp?profileid=7274.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.


* Onda M, Nagata S, FitzGerald DJ, Beers R, Fisher RJ, Vincent JJ, Lee B, Nakamura M, Hwang J, Kreitman RJ, Hassan R, Pastan I. Characterization of the B-cell epitopes associated with a truncated form of Pseudomonas exotoxin (PE38) used to make immunotoxins for the treatment of cancer patients. Journal of Immunology, December 15, 2006; Vol. 177, No. 12.

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