Therapeutic factor XI blockade for sepsis

DESCRIPTION (provided by applicant): This Phase I SBIR grant will support the initial commercial development of a single dose injectable biological product candidate, recombinant humanized anti-factor XI monoclonal therapeutic anticoagulant antibody, towards an investigational new drug (IND) application. The lead indication is severe bacterial sepsis, which is among the leading causes of mortality among hospitalized patients. Ischemia contributes to the pathogenesis of sepsis-associated disseminated intravascular coagulation (DIC) and systemic inflammatory response syndrome (SIRS). Antithrombotic drugs may be effective; however, their most potent doses can produce severe bleeding side effects. Apart from antibiotics, the only FDA-approved treatment for severe sepsis is the anticoagulant enzyme recombinant activated protein C (APC, Xigris(r)), but the bleeding side effects of APC outweigh its benefits in less severe cases. Our product candidate addresses a major medical need with a safe and effective alternative to APC. The molecular target is coagulation factor XI (FXI). FXI deficiency improves the survival of experimental polymicrobial peritonitis in mice, and preliminary data suggest that anticoagulation by antibody inhibition of FXI produces similar benefits. FXI inhibition may also be anti-inflammatory by reducing bradykinin liberation. Antibody inhibition of FXI represents a fundamentally new method of anticoagulation because FXI is part of the contact pathway where the molecular mechanisms of hemostasis and thrombosis converge. In primates, anticoagulation by antibody inhibition of FXI is antithrombotic for more than a week, and hemostatically safer than heparin or aspirin. No comparable drugs exist, and thus if AXIMAB is successfully developed, it would have significant market potential. The Specific Aims are to 1. Prepare neutralizing mouse anti-mouse FXI monoclonal antibody (mAXIMAB); 2. Determine the efficacy of mAXIMAB in septic mice; and 3. Determine the hemostatic safety of mAXIMAB in na ve mice. Positive results will support the hypothesis that pharmacological inhibition of FXI is beneficial in sepsis. PUBLIC HEALTH RELEVANCE: Thrombotic occlusion of blood vessels in sepsis causes ischemia and contributes to the high mortality rate of severe systemic inflammatory response syndrome. Antithrombotic drugs that could be effective produce severe bleeding side effects, which render them less than useful. Apart from antibiotics, the only FDA approved treatment for severe sepsis is the antithrombotic enzyme, recombinant activated protein C (APC, Xigris(r)), but bleeding side effects outweigh its benefits in less severe sepsis cases. We address this major medical need with a new antithrombotic antibody product candidate to provide a safe and effective alternative to APC.