PROTEASE FORMULATION BASED ON CROSSLINKED ENZYME CRYSTAL

设计新型高效的蛋白质药物传递系统是目前研究的热点之一。 现代生物技术和生物制药产业的重大主题。 我们发现交联的酶晶体（CLECs（R））显示出稳定性， 在低pH下，在储存和抗蛋白水解。CLEC可以是 以高产率制备并具有高蛋白质负荷。这些属性 使其成为肠腔内治疗的理想选择， 在腔内通道内进行，而不需要 治疗剂的全身生物利用度。病人会 吞咽CLEC颗粒的片剂或液体悬浮液， 所需的代谢酶或蛋白质。CLEC（R）代理将 在恶劣的酸性pH和蛋白水解环境中生存下来 胃，并通过近端小肠与保存 它的生化活性。CLEC（R）粒子将执行其 在肠腔内的治疗生物化学，同时保持耐药性 被内源性蛋白酶降解。在第一阶段研究中，我们 我建议开发一种在酸性条件下稳定的蛋白酶-CLEC， 胃的状况和高温（37摄氏度） 并且在蛋白水解酶存在下。Protease-CLEC将 在十二指肠中发挥作用，同时保持水晶状态 通过溶解CLEC材料或通过释放活性来释放CLEC颗粒。 选择该靶点是为了解决目前治疗的问题， 使用蛋白酶-CLEC和 Lipase-CLEC（我们已经开发）。此外，蛋白酶- CLEC也可能有助于治疗慢性胰腺炎的疼痛。如果 如果成功，这些方法将导致引入新的 高效的蛋白质运载工具。 拟议的商业应用： 目前，美国有10，000 - 13，000名慢性胰腺炎患者， 美国和世界其他地区的20,000人。此外还有 在美国和世界其他地区有45，000名CF患者。的 原型TheraCLEC-蛋白酶沿着TheraCLEC-脂肪酶具有 巨大的商业潜力超过目前可用的胰腺 酶产品以及用于自身免疫和 传染病全球市场目前为4亿美元 仅美国就提供了2亿美元

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.