Project Grant R43HL172567

TESTING NOVEL ADVANCEMENTS TO RECOMBINANT HEPARIN PRODUCTION - PROJECT SUMMARY HEPARIN IS AN ESSENTIAL DRUG, IN THE FORM OF A COMPLEX POLYSACCHARIDE, WHICH IS ROUTINELY USED IN THE CLINIC FOR TREATMENT AND PREVENTION OF THROMBOSIS. ABOUT 300,000 DOSES ARE ADMINISTERED DAILY IN THE UNITED STATES, AND THE WORLDWIDE MARKET FOR HEPARIN IS ABOUT $7B. PHARMACEUTICAL HEPARIN IS PURIFIED FROM PIG INTESTINES, SOURCED PRIMARILY FROM SLAUGHTERHOUSES IN CHINA. WITH HUNDREDS OF MILLIONS OF SLAUGHTERED PIGS, THE COST OF UNFRACTIONATED HEPARIN HAS BEEN EXTREMELY LOW. HOWEVER, SUPPLY CHAIN REGULATION IS DIFFICULT, AND LEAD TO THE HEPARIN CRISIS IN 2007 & 2008 DUE TO ECONOMICALLY MOTIVATED ADULTERATION OF CRUDE HEPARIN. THIS RESULTED IN OVER 200 DEATHS WORLDWIDE. THE PROBLEM WAS CAUSED BY BLUE EAR DISEASE, DECIMATING ASIAN PIG POPULATIONS AND DRIVING UP THE PRICES. MORE RECENTLY (2019), THE AFRICAN SWINE VIRUS OUTBREAK AGAIN DECIMATED ASIAN PIG POPULATIONS. CONGRESSIONAL LEADERS AND REGULATORY AGENCIES CONTINUE TO BE CONCERNED ABOUT ADULTERATION AND SHORTAGES AND OUR RECENT EXPERIENCE WITH PANDEMICS SHOULD BE A WARNING THAT RELYING ON FOREIGN ANIMAL POPULATIONS FOR AN ESSENTIAL DRUG IS TOO RISKY. AS AN ALTERNATIVE, TEGA HAS ENGINEERED A NOVEL MASTOCYTOMA CELL LINE (MST) TO PRODUCE RECOMBINANT HEPARIN WITH THE SAME ANTICOAGULANT ACTIVITY AS PORCINE DERIVED HEPARIN. LIKE OTHER BIOLOGICALS, RECOMBINANT HEPARIN IS PRODUCED UNDER COMPLETELY CONTROLLED CONDITIONS THAT SIGNIFICANTLY REDUCES THE RISKS OF SHORTAGES AND PROVIDES MORE CONSISTENT PRODUCTS. HIGHER STRUCTURAL CONSISTENCY WOULD REDUCE THE MAJOR HEPARIN SIDE EFFECT (BLEEDING). THROUGH CELL ENGINEERING, WE CAN ALSO REDUCE THE RISK OF HEPARIN INDUCED THROMBOCYTOPENIA (HIT), PERHAPS THE SECOND MOST IMPORTANT HEPARIN SIDE EFFECT. THUS, RECOMBINANT HEPARIN WOULD BE A PREMIUM PRODUCT IN A STRATIFIED MARKET AIMED AT PATIENTS UNDERGOING CARDIOPULMONARY BYPASS SURGERY AS WELL AS OTHER CRITICAL HOSPITAL PROCEDURES. OPTIMIZING PRODUCTION AND REDUCING COST ARE CRITICAL FOR INTRODUCING AN ALTERNATIVE TO PORCINE HEPARIN. HERE, TEGA PROPOSES TO COLLABORATE WITH SCIPERIO, AN ADVANCED MANUFACTURING COMPANY, USING THEIR TECHNOLOGY TO OPTIMIZE PRODUCTION. SCIPERIO USES A UNIQUE BIOREACTOR DESIGN WHICH FACILITATES GREATER CONTROL OVER CELL GROWTH AND PRODUCTION PARAMETERS AND ACTIVELY REMOVES WASTE PRODUCTS. FURTHERMORE, THESE BIOREACTORS CAN RECYCLE GROWTH FACTORS IN A NOVEL PROCESS THAT INCREASES CELL NUMBER WHILE REDUCING COST. GREATER CONTROL HAS PROVEN TO BE ESPECIALLY VALUABLE FOR ALTERNATIVES TO THE STANDARD PRODUCTION CELL TYPES (I.E., CHO, HEK293) WHICH IS A DIRECT BENEFIT FOR THE ENGINEERED MST CELL LINES PROPOSED HERE. ADVANCES IN THIS AREA WILL ADVANCE BIOLOGICAL MANUFACTURING FOR APPLICATIONS MORE COMPLEX THAN ANTIBODY PRODUCTION. THE GOAL OF THIS PROPOSAL IS TO OPTIMIZE THE GROWTH MEDIA AND GROWTH PARAMETERS OF OUR HEPARIN PRODUCING CELLS IN SCIPERIO'S ADVANCED BIOREACTOR FORMAT, INCREASING THE EFFICIENCY OF PRODUCTION, THUS REDUCING THE COST. THIS PROJECT IS DIRECTLY RELEVANT TO THE PRESIDENTS SEPTEMBER 12TH EXECUTIVE ORDER TRIGGERING BIOTECH AS A FRONT IN ECONOMIC COMPETITION WITH CHINA.