Peptide inhibition of complement-mediated hemolysis after xenotransfusion.

DESCRIPTION provided by applicant The hypothesis for this project is that a novel compound Peptide Inhibitor of complement C PIC will inhibit antibody initiated complement mediated cell destruction in a xenotransfusion animal model Complement is the most potent inflammatory cascade in humans and is initiated by antibodies driving classical pathway activation and host cell destruction in many inflammatory diseases One such disease is Acute Intravascular Hemolytic Transfusion Reaction AIHTR which is a highly lethal form of transfusion reaction Frequently transfused populations e g sickle cell disease are at greatly increased risk of AIHTR due to development of antibodies against minor erythrocyte antigens Currently no treatment exists to prevent or treat AIHTR besides supportive care and thus represents a critical unmet medical need including underserved populations like sickle cell disease patients We have developed a simple and robust model of AIHTR in rats which we will use to test PIC Our current lead compound of PIC PA CPEG is the product of years of rational drug design yielding a amino acid peptide conjugated with PEG Our compound binds to the initiating component of the classical pathway C efficiently blocking antibody initiated complement activation at the first step in the cascade PIC is delivered in a saline vehicle and has reproducibly shown in multiple dosing studies to block classical complement activation in rats This inhibition is rapid seconds and potent andgt inhibition of classical complement activation We have performed a pilot experiment using PIC to inhibit hemolysis of mismatched erythrocytes in our xenotransfusion protocol PIC demonstrated a dose dependent effect and at high dose profoundly inhibited complement mediated intravascular hemolysis to the same degree as the gold standard cobra venom factor CVF Thus this pilot experiment demonstrated that PIC can completely block antibody initiated classical complement mediated cell destruction The proposed studies will refine the dosing of PIC and then conduct fully powered studies to evaluate the efficacy of PIC in inhibiting AIHTR in the rat model We will test PIC in both a prophylactic strategy and an intervention treatment strategy The prophylactic treatment strategy will mimic the clinical scenario of the patient at high risk fo AIHTR who could potentially receive PIC prior to transfusion The intervention treatment strategy will mimic the clinical scenario where the transfusion begins and the patient develops fever diaphoresis and hypotension In addition to receiving epinephrine to support blood pressure the patient could also receive PIC to inhibit the mechanism of pathogenesis and prevent further hemolysis and acute kidney injury The success of the proposed studies will provide critical proof of concept that PIC can prevent complement mediated pathogenesis in an animal model of human disease This will provide the necessary evidence to propel the future pre clinical development of PIC through pharmacokinetic and toxicology studies PUBLIC HEALTH RELEVANCE The goal of the proposed research project is to conduct proof of concept testing of a promising novel anti inflammatory compound PIC in an animal model of transfusion reaction This compound inhibits a novel pathway of inflammation the complement cascade which is not targeted by current anti inflammatory drugs The proposed studies will optimize dosing and test whether PIC can prevent the destruction of mismatched transfused red blood cells in an animal model This will provide important information about whether PIC could potentially be used to prevent or stop a transfusion reaction in humans