7 December 1998 CapCure5\Bander.MS-- 900 words
Monoclonal antibodies work for other cancers,
seem ideal for prostate cancer too
Lake Tahoe, NV--Prostate cancer is "ideally suited" for monoclonal antibody therapy, said Neil Harrison Bander, MD. Phase I and Phase II studies have already demonstrated PSA responses in some patients.
And prostate-specific membrane antigen (PSMA) is the "ideal target," said Dr. Bander, at CapCURE'S 5th Annual Scientific Retreat here this September. They now understand PSMA better and have an improved antibody that targets the extracellular rather than the intracellular domain of the protein, he said.
"Monoclonal antibodies have already demonstrated clinical success in a number of different cancers which have many similar features to prostate cancer," said Dr. Bander, director of urologic oncology, New York Hospital-Cornell Medical Center.
The FDA has approved Rituxan for non-hodgkin's lymphoma and Herceptin for breast cancer. In Germany, Panorex has demonstrated effectiveness in colon cancer.
"Prostate cancer metastasizes predominantly to bone marrow and lymph nodes," said Dr. Bander. "These are sites which have been shown to be effectively treated by antibodies in other settings. These are sites which get high levels of circulating antibodies."
Furthermore, prostate cancer "tends to have a small volume of tumor, with metastatic sites measured in microns or millimeters, unlike other diseases where we're treating large multi-centimeter masses," said Dr. Bander. "Patients have a low tumor burden at the time of PSA failure. We can anticipate relapse years before PSA failure. And PSA failure occurs years before clinical failure."
A Phase I trial gave 19 patients Prost 30, the antibody used in Prostascint, with an I-131 tracer to track the distribution. "We showed that the antibody did in fact track specifically the tumor sites," said Dr. Bander. "Serendipidously and unexpectedly we found several patients who had PSA responses." In 7 patients who could be evaluated, 4 (57%) had PSA declines of greater than 50%.
"We followed that trial with a Phase I/II of naked antibody in 21 patients, all of whom had to have at least 3 sequentially rising PSAs prior to entry," said Dr. Bander. 23% of those patients had greater than 50% decline in PSA. "One patient still has a durable response over 3 years from the time of his treatment," he said.
In an adjuvant trial, 10 patients at high risk following radical prostatectomy, based on Gleason score and margin status, were given a single dose of antibody within 1 month post-surgery, and followed for a median 2.4 years, said Dr. Bander. The group had a PSA failure of 30%, compared to a PSA failure of 60% in the corresponding cohort in the Partin tables.
"The antibody itself seems to induce some anti-tumor effect in about one-quarter of the patients after a single dose," said Dr. Bander.
"We're going to drop the Prost 30 monoclonal antibody," said Dr. Bander. The original antibody to PSMA was developed several years ago. Since that time, "we know much more about PSMA." It's been cloned and sequenced, and its expression characteristics are well known, "and happen to be ideal."
PSMA is a membrane-spanning protein. The normal variant lacks a membrane-spanning region and so is expressed only inside the cell. When the cell is transformed, the membrane-spanning variant is expressed, most of it externally, with a small intracellular tail, said Dr. Bander. PSMA is expressed by a very high proportion of prostate cancers. The expression increases as the disease develops and becomes hormone independent.
In 1995 they realized that Prost 30 targets the intracellular part of the protein, and is not accessible to antibodies in living cells, said Dr. Bander. Presumably Prostascint is binding to dead cells which have spilled their contents. "We set out to make antibodies that will bind to a better epitope." They found 4 antibodies to 2 different epitopes, and developed one, which is still unnamed and designated simply J591. "Our antibody will bind to viable cells," he said. The PSMA-antibody complexes form clatherin-coated pits and the vesicles are internalized. PSMA is normally internalized into the cell, but the antibody triples the rate.
In addition to prostate cancer cells, PSMA is also expressed by tumor vascular endothelial cells, but not by normal endothelial cells. "That gives us the possibility of a sort of double whammy effect in prostate cancer," said Dr. Bander. "We can target not only cancer cells themselves but their blood supply."
"The naked antibody mouse version does mediate antibody-dependent cytotoxicity in the in vitro assay," said Dr. Bander. "We can show that the bismuth-213 conjugated antibodies effectively kill the LNCaP prostate cancer xenograft."
"So we have in vitro data and we have animal data," said Dr. Bander. "We've also genetically engineered a humanized version, so that we can treat patients multiple times." (Mouse antibodies can only be used once, because the human body develops immunity after the first time.)
"At the moment the mouse version is in Phase I clinical trials in hormone refractory prostate cancer patients," said Dr. Bander. "We got approval from the FDA and we've entered 4 patients. We're treating about a patient a week. I expect we'll complete the study at around 20-25 patients in February or March."
A small startup company, BZL Biologics, Inc., Framingham, MA, is a commercial sponsor of the project. Dr. Bander is a consultant to the company.