Anthrax is recognized as a class A bio-threat microbial pathogen that is readily weaponized and exceedingly difficult to treat. This bacterium is highly virulent inducing lethal infection in immunologically normal hosts by its intrinsic capacity to disseminate rapidly and induce sepsis, along with its ability to generate two highly potent exotoxins, lethal toxin and edema toxin. In phase I of our STTR grant, we successfully demonstrated that a unique set of plasma proteins from human blood collectively known as Inter-alpha inhibitor proteins (IAIP) can salvage susceptible mouse strains with established anthrax spore-induced bacterial sepsis when administered concomitantly with standard antimicrobial agents. The level of protection afforded was significantly greater than that observed by antibiotic therapy alone. The dual actions of IAIP against anthrax as a systemic protease inhibitor therapy for sepsis and a specific anthrax toxin inhibitor make it a potentially attractive treatment strategy for managing patients who are infected with anthrax. IAIP has a documented safety record in clinical medicine as this endogenous human protein has already been used in clinical trials in patients with sepsis and other systemic inflammatory states. This existing clinical data indicates that IAIP could be rapidly deployed in the event of a bioterrorist event for actual clinical use with a reasonable level of assurance of its safety and efficacy. This phase II STTR grant application will expand upon these promising findings and provide the necessary preclinical confirmation of the therapeutic value of this protein as a biodefense strategy against anthrax. The proposed studies will have three major aims.
The first aim i s to scale up production of highly purified IAIP for human use and determine the pharmacokinetics and pharmacodynamics of these human proteins in two animal models of anthrax intoxication.
The second aim will focus upon formulation and optimization studies of lyophilized IAIP to achieve a product with greater stability and the longer shelf life that is a prerequisite for the stockpile biodefense program.
The final aim of this project will be the preclinical testing of IAIP therapy in two established large animal models of anthrax infection to satisfy the """"""""Animal Rule"""""""" in the development of therapeutic agents against this biohazardous pathogen.
This Phase II STTR project is focused on the product development of inter-alpha inhibitor proteins for the protection of anthrax exposure from the possible occurrence of bioterrorism. The therapeutic proteins offer a unique, two-fold action by fighting the inflammation caused by exposure and targeting the cleaving enzyme responsible for anthrax toxicity.
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| Lee, Benjamin C; Mayer, Chad L; Leibowitz, Caitlin S et al. (2013) Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy. Blood 122:803-6 |
