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 Although originally deemed successful, Xigris was ultimately withdrawn due to lack of efficacy and an unacceptable bleeding risk.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.
Skip Nav Destination
Article navigation
August 2015
-
Cover Image
Cover Image
- PDF Icon PDF LinkTable of Contents
Review Article|
August 03 2015
Engineering activated protein C to maximize therapeutic efficacy
Louise M. Quinn;
Louise M. Quinn
*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
Search for other works by this author on:
Clive Drakeford;
Clive Drakeford
*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
Search for other works by this author on:
James S. O’Donnell;
James S. O’Donnell
‡Department of Haematology, School of Medicine, Trinity College Dublin, Dublin 8, Ireland
Search for other works by this author on:
Roger J.S. Preston
Roger J.S. Preston
1
*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
1To whom correspondence should be addressed (emailprestonr@tcd.ie).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
December 12 2014
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2015 Authors; published by Portland Press Limited
2015
Biochem Soc Trans (2015) 43 (4): 691–695.
Article history
Received:
December 12 2014
Citation
Louise M. Quinn, Clive Drakeford, James S. O’Donnell, Roger J.S. Preston; Engineering activated protein C to maximize therapeutic efficacy. Biochem Soc Trans 1 August 2015; 43 (4): 691–695. doi: https://doi.org/10.1042/BST20140312
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.