9 October 1997 UROT97\HER2PROS.MS-- 630 words
Bispecific antibodies shrunk a few tumors,
randomized trial for PCa starting
Lake Tahoe, NV--Another monoclonal antibody for cancer therapy is moving into human trials, for radical prostatectomy patients with HER-2/neu oncogene expression.
The phase II randomized trial will seek radical prostatectomy patients with tumor at the surgical margin or with seminal vesicle involvement, said Aaron E. Katz, MD, assistant professor of urology at Columbia University's College of Physicians and Surgeons, in New York City. The tumor must be expressing the HER-2/neu oncogene, he said.
Patients will receive a weekly IV infusion of humanized mouse monoclonal antibody for 6 weeks, said Dr. Katz, who described the trial at the Fourth Annual Scientific Retreat of The Association for the Cure of Cancer of the Prostate (CaP CURE) here this September. The trial will probably last 5 years, he said. The 5-year recurrence rate of tumor at the margin, or seminal vesicle involvement, is normally 40 to 60%, and the trial will seek to reduce that.
This is a bispecific antibody, said Dr. Katz. "It responds to 2 idiotypes," he said, "one on the target cell, the other on the surface of a macrophage." It emulates the natural immune response, and induces a killer T-cell response, he explained.
The first target, the HER-2/neu protein, is expressed on the outer surface of the cell membrane, said Dr. Katz. It is involved in oncogenesis, "and has been shown to correlate with poor prognosis in both prostate and breast cancer," he said.
The HER-2/neu oncogene and its protein (also known as c-erbB-2) is a tyrosine kinase receptor, which isn't found in detectable levels on normal cells, but sometimes appears on prostate, bladder, renal, breast, ovarian, colon and other cancers.
The second target is a high-affinity Fc receptor on the surface of monocytes, macrophages and activated neutrophils that triggers killing of targeted tumor cells or pathogens. The 2 antibodies are created separately and then bound together.
The bispecific antibodies, developed by David Segal, MD, of the National Cancer Institute, can bring the 2 cells together. Beyond that, the antibodies are engineered to bind to a specific adhesion molecule on killer T cells that activates the killer cells to destroy the cancer cell.
The antibody, currently designated MDX-210 or MDXH210, is manufactured by Medarex, Inc., Annendale, NJ, which has collaborations with E. Merck of Germany and Ciba-Geigy of Switzerland, and is sponsoring the trials.
In phases II studies, MDX-210 reduced metastases in 2 (of 4) kidney cancer patients and lowered PSA by over 90% in 1 metastatic prostate cancer patient, according to a report at the University of Birmingham, UK, by Philip Atherton, MD, at the 5th International Bispecific Antibody Conference in Volendam, The Netherlands this June.
"The phase I and phase II data show that the toxicity of the treatment is mainly flu-line symptoms," said Dr. Katz, "fever, chills, symptoms that you would see with other types of systemic therapy." The antibodies are created in mice, but "humanized" to eliminate the anti-mouse immune reactions that limited earlier antibody therapy.
In normal antibodies, the Fc, or constant, end of the antibody binds to the Fc receptor on the immune system effecter cells. But in the MDX-210 antibody, the Fc ligand is made from a variable region, rather than the constant region. And the Fc ligand is modified so that it doesn't bind to the normal binding site, and so doesn't have to compete with all the other circulating antibodies, explained Lisa N. Drakeman, vice president at Medarex. The MDX-210 antibody "arms" monocytes, which are precursors to macrophages, and stimulates cytokines such as tumor necrosis factor-alpha.
"This is an interesting way of treating patients using immune therapy rather than hormonal or radiation therapy," said Dr. Katz.