This Phase I/II Fast-Track application is being re-submitted under the NHLBI Small Business Topics of Special Interest for Fiscal Year 2016 (HLS16-04). Certain life-saving interventions such as cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), or ventricular assist device (VAD) pump require the use of high dose heparin to maintain blood flow through the devices and/or to prevent downstream thromboembolic complications. Several other invasive vascular procedures also utilize profound temporal anticoagulation, such as during and after prosthetic vascular graft implantation. Unfortunately, antithrombotic agents such as heparin inadvertently target vital hemostatic molecular mechanisms and can produce severe dose-limiting hemorrhagic toxicity. Consequently, the level of anticoagulation must be limited to balance the risk of bleeding with thrombosis. As a result, thrombotic complications can be frequent and devastating. Our recent studies suggest that coagulation factor XII (FXII) contributes to the progression of thrombosis, and thereby is a potential target for a new class of antithrombotic drugs. Since data suggests that FXII does not contribute to hemostasis, and FXII deficiency is an asymptomatic condition in mammals, FXII inhibition is unlikely to have significant adverse effects. We have generated a proprietary murine monoclonal antibody, 15H8, against human FXII that was created by immunizing FXII knockout mice, and verified its anticoagulant and antithrombotic effects in preliminary primate experiments. This proposed Phase I/II Fast-Track project will initiate the commercial development of a recombinant humanized version of 15H8 (rh15H8), a product candidate that could be used as a stand alone or as an adjuvant anticoagulant to increase the antithrombotic efficacy of heparin without further increasing heparin-associated bleeding risks.
The Specific Aims for this project that will be necessary to support 15H8 development towards an investigational new drug (IND) application are to: 1) Evaluate the antithrombotic effect of the murine anti-FXII antibody (15H8) in a primate model of experimental extracorporeal membrane oxygenation (ECMO), 2) Determine the activity and efficacy of recombinant humanized 15H8 (rh15H8), and 3) Manufacture rh15H8 for use in GLP toxicity studies. The rh15H8 approach represents a fundamentally new therapeutic anticoagulation concept since FXII inhibition is expected to reduce the formation of contact-initiated blood clots in synthetic grafts and extracorporeal devices without a detrimental effect on residual bleeding control in critically ill, anticoagulated patients. Success of this project and reaching our critical milestones will lead directly to the next stage of product development that will consist of GLP toxicity and stability studies, IND preparation and filing, followed by the initiation of phase 1 first- in-human safety studies of our innovative antithrombotic drug candidate.

Public Health Relevance

The blood-thinner heparin has long been used to prevent blood clot formation during certain life-saving procedures such as extracorporeal membrane blood oxygenation in patients whose lungs fail, or during open- heart surgeries, but heparin can have severe bleeding side effects and is often not fully effective. Consequently, there remains an urgent unmet medical need for improving the safety and effectiveness of anticoagulation during interventional vascular procedures. The proposed research addresses this need by engaging in the development of a new anticoagulant antibody drug candidate, rh15H8, which does not affect hemostasis (bleeding control), but has antithrombotic effects, and therefore could be used alone or to safely enhance the effectiveness of heparin.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Warren, Ronald Q
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Aronora, Inc.
United States
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Zilberman-Rudenko, Jevgenia; Sylman, Joanna L; Lakshmanan, Hari H S et al. (2017) Dynamics of blood flow and thrombus formation in a multi-bypass microfluidic ladder network. Cell Mol Bioeng 10:16-29