By Frances Bishopp
Although rejection endangers tissue transplant patients, certain areas of the body are safe from the threat due to a protein called Fas ligand, first identified by CERES Pharmaceuticals Ltd., a start-up biotech company located in Denver.
Funded by several grants from the National Institutes of Health and a Phase I Small Business Innovative Research (SBIR) grant, CERES opened its doors in 1995 expressly to develop therapeutic products that stimulate and suppress the human immune system.
CERES currently has five employees and is headed up by president, Richard Duke, who is on leave from his position as an assistant professor of medicine and immunology at the University of Colorado Health Sciences Center.
“We have identified a molecule called Fas ligand,“ Duke told BioWorld Today, “which we are going to use to suppress the immune system and fight tumors.“
Resting T cells produce low levels of Fas, which spans the cell membrane and projects into the extracellular space at one end and into the cell’s interior at the other end, where it can convey signals deeper into the cell, Duke explained.
When T cells first encounter an antigen and become activated, they make extra, but initially nonfunctional Fas. They also temporarily make another surface molecule called Fas ligand.
After a few days, Fas becomes operational, Duke said. Then Fas ligand on activated T cells binds to Fas on the same cell or on other activated T cells at the site of infection and the binding instructs the Fas-bearing cell to undergo apoptosis.
Apoptosis, Duke explained, is helping scientists to understand that human health depends not only on the body’s ability to make new cells but also on the ability of cells to self destruct when they become damaged, diseased or unnecessary.
The failure of cells to undergo apoptosis can lead to abnormal proliferation of cells such as in cancer or other diseases.
Several tissues of the body are immune privileged, Duke said. These tissues appear to use Fas ligand to avoid becoming targets of autoimmunity. By displaying Fas ligand, certain cells in the testis, eye and brain induce rapid apoptosis in any Fas-bearing activated T cell that comes their way.
“The reason these tissues are immunologically privileged is they express ligand,“ Duke said. “This discovery could expand organ transplantation.“
“Drugs used today for transplants shut down the immune system and stop every sort of immune response, which can lead to infections, disease and even cancer,“ Duke said. “Fas ligand only wipes out designated cells. In animals, on which we have done extensive testing, you don’t have to use immunosuppressive drugs,“ Duke said.
In working with islet cell transplantation, a treatment for Type I diabetes, Duke said, they have used Fas ligand to protect transplants of the insulin-producing cells of the pancreas, in diabetic mice. This finding, Duke said, opens the door to a possible treatment for the 700,000 people in the U.S. with insulin-dependent diabetes.
CERES’ lead products are targeted at preventing transplant rejection, suppressing autoimmune diseases and treating certain cancers. First of the three is CD95 (Fas) Ligand-based Immunosuppression, which focuses on the clinical application of a mammalian, cell-derived, protein which has been shown to be effective in preventing transplant rejections.
Another product is CERES-Vax Vaccine Delivery System, which focuses on a recombinant-yeast-based vaccine delivery system. Pilot studies in mice and privates, Duke said, have shown that this system induces both humoral and cellular immune responses.
CERES’ third product is T Cell Protease Inhibitors, which focus on the discovery and clinical application of drugs which inhibit T cell proteases involved in protein production, including the HIV envelope protein.
CERES intends to secure its first round of seed financing ($200,000 to $500,000) from private investors and plans to apply for additional SBIR grants to sustain the company’s research and development efforts through 1999.
The company is pursuing collaborative research agreements and venture capital is being sought of at least $3 million to $5 million.