SBIR-STTR Award

Anticoagulation with heparin is intrinsic to virtually every procedure involving vascular injury or vascular manipulation, such as arterial bypass or angioplasty. Heparin,a polydisperse, sulfated polysaccharide possesses numerous other biological activities, including the ability to inhibit smooth muscle cell proliferation. Cationic protamine, has been used since 1939 to reverse heparin induced anticoagulation, but protamine therapy is frought with severe complications including exacerbation of smooth muscle cell proliferative lesions at sites of vascular injury. It is our assertion that a world-wide market exists for a safe protamine replacement which in principal, will specifically neutralize heparin' s conventional. anticoagulant properties without causing deleterious side- effects. Commonwealth Biotechnologies, Inc. (CBI) has developed four lead compounds which display high affinity for anticoagulant heparin which function in vivo to neutralize heparin's anticoagulant effects. In Phase I, we will continue to optimize the structures of our lead compounds and demonstrate their efficacy in vitro and in vivo. Their effect on smooth muscle proliferation and their usefulness in physiologically relevant surgical situations will be examined. These studies will form the basis for expanded and continued work in Phase II.

Thesaurus Terms:
biomaterial development /preparation, heparin, inhibitor /antagonist blood coagulation, hemostasis, pharmacokinetics, protamine calorimetry, circular dichroism, laboratory rabbit, tissue /cell culture

Anticoagulation with heparin is intrinsic to virtually every procedure involving vascular injury or vascular manipulation, such as arterial bypass or angioplasty. Heparin,a polydisperse, sulfated-polysaccharide possesses numerous other biological activities, including the ability to inhibit smooth muscle cell proliferation. Protamine, a cationic protein isolated from salmon sperm, has been used since 1939 to reverse heparin induced anticoagulation, but protamine therapy is fraught with severe complications including exacerbation of smooth muscle cell proliferative lesions at sites of vascular injury, allergic responses and in some cases, death. In Phase I, Commonwealth Biotechnologies Inc., examined the physicochemical properties, and the in vitro, ex vivo, and in vivo efficacies of specifically designed compounds with respect to their ability to bind anticoagulant heparin, their plasma clearance rates, and their biological effects on vascular smooth muscle cell viability and proliferation. Molecular modeling combined with biophysical assays, such as isothermal titration calorimetry, confirmed the design strategy of our best heparin binding compound. Factor Xa and aPTT assays confirmed the ability of these compounds to neutralized heparin induced anticoagulation. Studies in the guinea pig showed the ability of the compounds to reverse heparin-induced anticoagulation in the intact animal. The results obtained in Phase I form the basis for continued work in Phase II wherein additional synthesis and testing of new heparin binding structures will be done, and where the best compound will be developed to the point where a joint alliance, or outright license, can be secured with a pharmaceutical (or other) company which can take the compound through full scale animal and human trials. PROPOSED COMMERCIAL APPLICATION: There is a worldwide need for a heparin antagonist to replace protamine, which has severe hematological and immunological adverse reactions in the dosed patient. CBI has created specifically designed compounds which are effective heparin binding agents and which are functional in vivo. In Phase II, additional synthesis and testing will be done and our compounds developed to the point where outright license or a joint alliance can be secured for large scale animal and initial human trials.

Thesaurus Terms:
drug design /synthesis /production, heparin, inhibitor /antagonist cardiovascular pharmacology, chemical model, computer simulation, model design /development, pharmacokinetics, vascular smooth muscle calorimetry, dog, guinea pig