Preparation and development of a stabilized C3 analog for the treatment of paroxysmal nocturnal hemoglobinemia

Abstract We propose to develop analogs of human complement Cthat have the ability to form a stable CconvertaseIn additionthese proteins will be designed to decrease the affinity of the proteins for factor H bindingAll proteins will be expressed in the Baculovirus insect protein expression systemand tested for their ability to form a stable Cconvertase enzyme that is able to deplete complement in human serumThey will also be tested for their resistance to cleavage by complement factors H and IProteins that can form stable and active Cconvertases that are resistant to cleavage by complement factors H and I will be tested in in vitro pharmacokineticsstabilityand aggregation studiesIn Phase II of this applicationwe will test these proteins for their ability to protect PNH erythrocytes against lysisand in animal modelsWe will also commence GMP production of the protein and initiate IND enabling developmentincluding preclinical immunogenicity assessmentto prepare for Phase I clinical trials Project Narrative The complement arm of the innate immune system is implicated in paroxysmal nocturnal hemoglobinuriaPNHThis project will create and test a modification of human Cfor medical utility to abrogate the systemic damage caused by complement activation in PNHThis new complement treatment is expected to greatly improve the standard of care for PNH