Improved Antithrombin III for Circulatory and Cardiovascular Diseases

Blood vessels are lined with heparin-like molecules that serve an anticoagulant function and help to keep blood flowing through the circulatory system. Many artificial vessels and medical devices also feature heparin-coated surfaces that prevent blood clot formation and sustain flow. Heparins require the binding of antithrombin III (ATIII), an endogenous plasma protein, to express their anticoagulant properties. Under inflammatory conditions, endogenous ATIII can break down, allowing clotting to increase, which contributes to occlusive and disseminated intravascular coagulation (DIC) syndromes. This invention reports a newly developed recombinant human ATIII. Compared to endogenous ATIII, the recombinant form (1) can activate heparin at lower doses, (2) is more effective at binding the lumen of blood vessels and biomaterial surfaces, and (3) is more resistant to inflammatory inactivation. These engineered improvements in ATIII should permit its use at low doses for preventing blood flow reductions in patients who are at risk for occlusion (e.g., kidney dialysis, angioplasty, stent, vascular graft and ventricular assist device patients). This recombinant ATIII should also be useful for the reversal of DIC in inflammatory settings such as SIRS, sepsis and cardiopulmonary bypass.

60,000 people die from blood clots in the United States each year, making blood clots a more common cause of death than breast cancer. The market has seen $5.5 billion in sales from drug-eluting stents this year, a 36% gain from 2004. This invention concerns a new antithrombin III molecule that is useful for preventing blockage of natural and artificial blood vessels under a wide range of normal and pathological blood flow conditions.

Stage of Development
*The IP portfolio for this invention consists of PCT/US99/10549, PCT/US03/17506, and PCT/US2005/000843 covering variant forms of antithrombin III, and the use of these molecules under conditions of physiologic and pathologic blood flow.
*The enhanced activity of the recombinant ATIII has been demonstrated in vitro while current research is to show efficacy in animal models. The technology is available for licensing and/or developmental support under exclusive or non-exclusive terms.

Additional Info
*Schedin-Weiss S, et. al. Roles of N-terminal region residues Lys11, Arg13, and Arg24 of antithrombin in heparin recognition and in promotion and stabilization of the heparin-induced conformational change. Biochemistry 43(3): pp 675-83 (Jan 27, 2004).
*Jairajpuri MA, et. al. Antithrombin III phenylalanines 122 and 121 contribute to its high affinity for heparin and its conformational activation. J Biol Chem. 278(18): pp 15941-50 (May 2, 2003).
*Olson ST, et. al. Identification of critical molecular interactions mediating heparin activation of antithrombin: implications for the design of improved heparin anticoagulants. Trends Cardiovasc Med. 12(5): pp 198-205 (Jul 2002).

Inventor(s): Veronique Picard, Pedram Zendehrouh, Adrian Hobden, Susan Bock

Type of Offer: Licensing

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