A new generation of diagnostic tests, recently approved by the FDA, were created with the help of a technology patented by the National Institute of Dental and Craniofacial Research. Dr. Frank Robey, a senior investigator in NIDCR's Division of Intramural Research, developed a chemical procedure that facilitates the creation of complex, custom-designed peptides and peptide-based reagents. The method was licensed to Diatide Inc., a Londonderry, New Hampshire pharmaceutical company that is using the process to develop in vivo imaging tests and targeted therapeutics based on synthetic peptides linked to radioisotopes. One of the approved tests recognizes life-threatening blood clots and the other detects the presence of malignancy in lung masses that show up on routine chest X-rays.
Both of the test kits, AcuTectä for clots and NeoTectä for lung tumors, received FDA priority review status and were approved for use in humans in less than 12 months, reflecting the importance of this diagnostic technology in serving unmet medical needs. The company hopes that the new imaging tests will immediately help two groups of patients--those at risk of potentially fatal pulmonary emboli, and those who would normally require a biopsy to identify a lung tumor as benign or malignant.
"Dr. Robey's peptide technology unquestionably speeded up the discovery and development process for our diagnostic kits," said Dr. Richard Dean, CEO of Diatide. If we had relied on traditional chemical procedures, a small company like Diatide would not have had the resources to accomplish what we have done. This technology has definitely enhanced the rate of drug discovery."
A technique that can streamline the production of designer peptides has broad application throughout the biomedical sciences, according to Robey. "These two diagnostic kits are just the tip of the iceberg," he said. "This is an 'enabling technology' whose research and clinical applications are virtually limitless." Already, Phase II clinical trials are underway using AcuTectä to image acute clots in the carotid artery, which may prove to be an indicator of stroke risk, and NeoTectä for identifying malignancy in breast tissue.
AcuTectä
The first test kit, trade named AcuTectä, was approved for clinical use by the FDA in September 1998. AcuTectä is a test for deep vein blood clots, which can develop in the arms and legs as a result of trauma, surgery, or inactivity. The test is also very useful for detecting clots that can be associated with artificial hip and knee replacements. It is a major advance over traditional methods like venography, ultrasound, and MRI, all of which are sensitive methods for detecting clots, but none of which can distinguish between new and old clots. AcuTectä recognizes only freshly formed clots, which are much more unstable than the older clots and therefore more likely to dislodge, migrate to the lungs, and lead to a pulmonary embolism. Pulmonary emboli kill as many as 100,000 Americans each year.
The Diatide scientists used Robey's technology to construct a cyclic peptide that specifically binds to a platelet receptor that is only present in fresh clots. When the peptide is linked to a radioisotope called Technetium 99 (Tc99), these clots can be readily seen with a gamma camera, similar in principle to X-ray equipment. The ability of the peptide-based test to pinpoint the most dangerous clots can help direct clinicians to a proper treatment course.
NeoTectä
The NeoTectä kit is the latest to receive FDA approval, given the go-ahead for clinical use on August 4, 1999. The test is intended to help physicians distinguish between benign and malignant lung masses that are initially detected by X-ray. There are an estimated 170,000 new cases of lung cancer in the U.S. each year, and the new test represents a significant leap in diagnosis over previous procedures. Standard tumor diagnosis involves invasive lung biopsy and carries a 14 percent complication rate. In addition to patient comfort, the NeoTect test affords significant cost savings over biopsy. NeoTectä, like AcuTectä, involves a simple injection into the arm followed by a painless imaging procedure one to two hours after the injection.
The NeoTectä kit is based on somatostatin, a cyclic peptide naturally produced in the body. Somatostatin binds intensely to malignant lung tumors, which overexpress the somatostatin receptor, but does not bind to benign tumors. To produce NeoTectä, Diatide scientists produced a synthetic somatostatin and then used Robey's method to link the Tc99 isotope onto the peptide.
The next phase of development for NeoTectä will be the creation of a therapeutic peptide or "Theratideä". Instead of tagging on a low-energy isotope, such as Tc99, which allows clinicians to merely see a cancerous tumor, Diatide researchers have attached a high energy-emitter called Rhenium (Re75), which kills the tumors on site. Preliminary studies with Re75-tagged probes have been highly successful in killing lung tumors in mice. The procedure completely removed lung tumors with no deleterious side effects. A similar approach has produced encouraging results in reversing an aggressive pancreatic tumor in mice, and therapeutic trials using this Theratideä against melanoma and breast cancer are under development.
The chemistry that facilitated the development of the new imaging tests is the brainchild of Dr. Robey, Ray Fields, his assistant at the time, and former Visiting Associate, Dr. Wolfgang Lindner. In 1991, Robey and his colleagues patented a method by which synthetic peptides could be linked together in a precise manner or joined to other molecules at defined locations along the peptide chain.
The investigators accomplished this feat by developing a chemical procedure that incorporated "chloroacetyl" or "bromoacetyl" groups at strategic locations in a synthetic peptide chain. Properly placed, these highly reactive compounds permit peptides to be linked in a "head-to-tail" arrangement, resulting in the formation of cyclic peptides or peptide polymers. The reactive groups also provide sites for attaching various other materials, such as radioactive molecules. This powerful technology allowed peptides to be manipulated in ways that formed the basis of Diatide's new imaging kits.