Clinical Studies of a Human Monoclonal Antibody to TRAIL Receptor-1 Cleared by the U.S. Food and Drug Administration
ROCKVILLE, Md., April 30 /PRNewswire-FirstCall/ -- Human Genome Sciences, Inc. (Nasdaq: HGSI - news) announced today that it has received clearance from the U.S. Food and Drug Administration (FDA) of its Investigational New Drug (IND) application to begin trials of a novel anticancer drug. The drug is a human monoclonal antibody that specifically recognizes the TRAIL Receptor-1 protein, found on the surface of a number of cancer cells. The drug is called the TRAIL Receptor-1 human monoclonal antibody (TRAIL-R1 mAb). Human Genome Sciences will now proceed with a Phase 1 trial of TRAIL-R1 mAb. The trial will be an open-label, dose-escalating study to evaluate the safety and pharmacology of the drug in patients with advanced tumors.
TRAIL-R1 mAb is the fifth compound for treatment of cancer to emerge from Human Genome Sciences' laboratories into clinical development. The other drugs are LymphoRad(TM) for the treatment of B-cell cancers(1), Albuferon(TM) for the treatment of chronic myelogenous leukemia and a broad range of other cancers(2), Albuleukin(TM) for the treatment of solid tumors(3), and Repifermin for the treatment of cancer therapy-induced mucositis(4). Cancer treatment is emerging as a major focus of our clinical drug development activities.
TRAIL-R1 mAb is a classic example of genomic discovery. We originally searched for genes with similarity to tumor necrosis factors found to be expressed on the surface of a number of tumors. We identified TRAIL Receptor-1 as a member of the tumor necrosis factor receptor family of proteins.(5,6) Our original studies, as well as those by others, show that the TRAIL Receptor-1 protein is expressed on a number of solid tumors and tumors of hematopoietic origin. It has been demonstrated that such tumors are sensitive to killing by apoptosis induced by binding to TRAIL (tumor necrosis factor related apoptosis-inducing ligand)(6) and to TRAIL-R1 mAb(7).
TRAIL-R1 mAb is a human monoclonal antibody. The antibody chosen for clinical study was selected for its ability to mimic the effect of TRAIL. TRAIL-R1 mAb specifically recognizes the TRAIL Receptor-1 protein. Binding of TRAIL-R1 mAb to TRAIL Receptor-1 triggers cell death. Our scientists have demonstrated that tumors expressing TRAIL-R1 are sensitive to killing by apoptosis induced by binding to TRAIL-R1 mAb. In animal models, TRAIL-R1 mAb has demonstrated effectiveness in treating human breast, colon and uterine cancers. Unlike the natural TRAIL ligand, TRAIL-R1 mAb does not bind to the surface proteins DcR1 and DcR2 or the soluble receptor osteoprotegerin that act as TRAIL decoys.(8) TRAIL binds to these decoy proteins, but such binding does not trigger cell death.
The TRAIL-R1 human monoclonal antibody was made in a collaboration between Human Genome Sciences and Cambridge Antibody Technology. The drug will be produced in the Human Genome Sciences clinical manufacturing facility located in Rockville, Maryland. Human Genome Sciences holds the commercial rights to the drug.
Eric Rowinsky, M.D., Director of Clinical Research at the Institute for Drug Development of the Cancer Therapy and Research Center in San Antonio, Texas, said, "While the biological functions of TRAIL itself remain incompletely defined, the scientific literature provides strong evidence of TRAIL's ability to trigger cell death in numerous cancer cell lines with a high degree of selectivity and with minimal activity against normal cell types.(6) TRAIL-R1 mAb, an agonistic antibody to TRAIL Receptor-1, appears to display similar activities. It may also offer certain therapeutic advantages due to its significantly longer circulating half-life and its greater specificity. We look forward to exploring the potential of TRAIL-R1 mAb in treating cancer patients."
Craig A. Rosen, Ph.D., Executive Vice President, Research and Development, Human Genome Sciences, said, "The emergence of death receptors as targets for anticancer research has generated considerable excitement in the oncology community. TRAIL Receptor-1 was first discovered by Human Genome Sciences. We decided to take the approach of developing human antibodies that would stimulate the receptors to cause cell death as does the TRAIL ligand, but with the advantage of a longer half-life and the potential for greater efficacy. TRAIL-R1 mAb is an agonistic antibody that stimulates activity. To my knowledge, TRAIL-R1 mAb is the first human agonistic antibody to enter clinical trials."
David Stump, M.D., Senior Vice President, Drug Development, said, "We believe that TRAIL-R1 mAb has significant potential for use in treating a broad range of cancers and look forward to investigating its use in clinical trials. Preclinical studies suggest that TRAIL-R1 mAb may have therapeutic benefit in the treatment of human malignancies either as a single agent or in combination with chemotherapy. Following completion of this initial Phase 1 study, we hope to explore the use of TRAIL-R1 mAb in treating a number of tumor types."
William A. Haseltine, Ph.D., Chairman and Chief Executive Officer, said, "I am pleased to announce the initiation of clinical trials of this exciting new drug, TRAIL-R1 mAb. The mechanism of action of this drug is novel. It binds to a 'cell death' receptor that is expressed in a number of tumors, including tumors of the colon, breast, lung, stomach, cervix and uterus, in addition to cancers of hematopoietic origin. I view the development of this drug as a model of how genomics coupled to antibody technology can produce high quality clinical candidates."... |
