PROTEASE FORMULATION BASED ON CROSSLINKED ENZYME CRYSTAL

Design of new efficient drug delivery systems for proteins is one of the major themes of modern biotechnology and biopharmaceutical industry. We found that crosslinked enzyme crystals (CLECs(R)) show stability under low pH, on storage and against proteolysis. The CLECs can be prepared in high yield and have high protein load. These properties make them ideal for gut lumenal therapy where the therapeutic action is performed within an endolumenal channel without the need for systemic bioavailability of the therapeutic agent. The patient would swallow a tablet or liquid suspension of CLEC(R) particles composed of a needed metabolic enzyme or protein. The CLEC(R) agent would survive the harsh acidic pH and proteolytic environment of the stomach, and pass into the proximal small intestine with preservation of its biochemical activity. The CLEC(R) particle would then carry out its therapeutic biochemistry within the gut lumen while remaining resistant to degradation by endogenous proteases. In this Phase I study, we propose to develop a Protease-CLEC that will be stable under acidic condition of the stomach and at elevated temperature (37 degrees C) and in the presence of proteolytic enzymes. The Protease-CLEC will perform its action in the duodenum while remaining as crystalline material or by release of activity by dissolution of the CLEC particle. This target was chosen to address the problems of current therapies of pancreatic insufficiency using a combination of Protease-CLEC and Lipase-CLEC (which we already developed). In addition, Protease- CLEC may also help for the treatment of pain in chronic pancreatitis. If successful, these approaches will lead to the introduction of novel efficient protein delivery vehicles. PROPOSED COMMERCIAL APPLICATIONS: Currently, there are 10,000-13,000 Chronic Pancreatitis patients in the US and an additional 20,000 in the rest of the world. In addition, there are 45,000 CF patients in the US and the rest of the world. The prototype TheraCLEC-protease along with TheraCLEC-lipase has enormous commercial potential over the currently available pancreatic enzyme products as well as for adjuvant therapy in autoimmune and infectious diseases. The worldwide market is currently $400 million with $200 million from the US alone.