HanAll has developed a process and technique, Resistein™, involving the engineering of the native protein to significantly increase the half-life and bioavailability. Through its high throughput Resistein™ technology, parent molecules are modified by amino acid substitution to produce resistance to proteases in tissue, serum and GI track while maintaining or significantly improving their PK/PD profile. With molecules that are resistant to proteolysis, the goal is to produce the next generation of injectable proteins with superior efficacy and PK profiles compared to current proteins but also to develop the first generation of oral protein therapeutics.
The pharmacokinetic profile of protein therapeutics is highly related to protein stability. The stability of a protein in vivo is highly affected by proteolysis in tissue/blood and the digestive tract especially in the case of oral delivery. Proteolysis is a highly defined and structured process in which digestion occurs at a proteolysis trigger site(s), defined ‘entry site(s)’, on the protein and follows a specific pathway down to protein fragments. Amino acid substitution at the ‘entry sites’ may result in a protein’s resistance to proteolytic degradation, without altering its biological activity. Thus, HanAll’s proprietary process of ‘domain engineering’ and ‘single point mutations at the entry sites’ inhibits proteolysis and render bioavailability and orders of magnitude greater potency and longer half-life compared to native proteins when administered orally.
Background and unmet needs
Many companies have been trying to develop human thrombopoietin as an injectable form to find a cure for thrombocytopenia. However, since the needle-based delivery accompanies pain, infection, and other risk factors, alternative methods such as prolonged dosage interval or oral administration have been attempted. Increased stability of human thrombopoietin is prerequisite to meet these goals while the protease activity remains the major set back in solving the problems ahead. In this circumstance, one of the most important aim of developing oral therapeutic protein is to generate a protease resistant form of a protein with low molecular weight, and retaining its biological activity as well.
Discovery and Achievements
Modified TPO shows enhanced resistance to protease existing in serum and tissue and activates signal pathway for proliferation and differentiation of megakaryocytes through binding to c-mpl (TPO receptor).