title: Engineering activated protein C to maximize therapeutic efficacy.
abstract: The anticoagulant-activated protein C (APC) acts not solely as a crucial regulator of thrombus formation following vascular injury, but also as a potent signalling enzyme with important functions in the control of both acute and chronic inflammatory disease. These properties have been exploited to therapeutic effect in diverse animal models of inflammatory disease, wherein recombinant APC administration has proven to effectively limit disease progression. Subsequent clinical trials led to the use of recombinant APC (Xigris) for the treatment of severe sepsis. Although originally deemed successful, Xigris was ultimately withdrawn due to lack of efficacy and an unacceptable bleeding risk. Despite this apparent failure, the problems that beset Xigris usage may be tractable using protein engineering approaches. In this review, we detail the protein engineering approaches that have been utilized to improve the therapeutic characteristics of recombinant APC, from early studies in which the distinct anti-coagulant and signalling activities of APC were separated to reduce bleeding risk, to current attempts to enhance APC cytoprotective signalling output for increased therapeutic efficacy at lower APC dosage. These novel engineered variants represent the next stage in the development of safer, more efficacious APC therapy in disease settings in which APC plays a protective role.
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 8, Ireland National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Dublin 12, Ireland.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Quinn
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 8, Ireland National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Dublin 12, Ireland.
authors.forename: Clive
authors.initials: C
authors.lastname: Drakeford
authors.affiliation: Department of Haematology, School of Medicine, Trinity College Dublin, Dublin 8, Ireland.
authors.forename: James S
authors.initials: JS
authors.lastname: O'Donnell
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 8, Ireland National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Dublin 12, Ireland prestonr@tcd.ie.
authors.forename: Roger J S
authors.initials: RJ
authors.lastname: Preston
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D011486:Protein C / Q000235:genetics / Q000378:metabolism*; D015202:Protein Engineering / Q000379:methods*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D011486:Protein C; D011994:Recombinant Proteins
keywords: activated protein C; anti-coagulant; inflammation; protease-activated receptor 1; sepsis