Modification of clearance of therapeutic and potentially therapeutic proteins

Current Drug Targets. Cardiovascular & Haematological Disorders
William P Sheffield

Abstract

Advances in biochemistry, protein chemistry and molecular biology over the last twenty-five years have spurred the increased use and development of proteins as injectable therapeutic agents. Introduction of proteins into the circulation exposes them to numerous different cells, enzymes and routes of extravasation that contribute to their clearance and their catabolism. Overly rapid clearance, particularly of small proteins, can limit therapeutic efficacy. Many strategies have been devised to retard the clearance of therapeutic or potentially therapeutic proteins, but relatively few proteins with clearance-retarding modifications are in clinical use. Proteins have been chemically modified towards this end by covalent attachment of polyethylene glycol or dextran chains or by protein-protein cross-linking. Genetic modification has also been employed to fuse proteins of interest to long-lived plasma proteins like albumin or immunoglobulins, or portions of these proteins. While all modifications may reduce the biological activity of the protein of interest or elicit antibody formation in recipient animals or patients, there now exists sufficient experience in this area that an optimal clearance-extending strategy can often be design...Continue Reading

Citations

Jun 24, 2006·Biotechnology Letters·Ray Bakhtiar, Ziqiang Guan
Feb 18, 2004·The Journal of Laboratory and Clinical Medicine·Teresa R McCurdyWilliam P Sheffield
May 12, 2012·The Journal of Biological Chemistry·Amber A BentleyAnton A Komar
Dec 13, 2006·Oligonucleotides·Paula E BurmeisterAnthony D Keefe
Apr 29, 2008·Acta Biomaterialia·Joel L KaarAlan J Russell
Aug 4, 2004·British Journal of Haematology·William P SheffieldFrederick A Ofosu
Sep 2, 2004·Journal of Addictive Diseases·Lon R Hays
Apr 13, 2010·The Journal of Physical Chemistry. B·Vadakkancheril S JishaDanaboyina Ramaiah
May 8, 2004·Archives of Biochemistry and Biophysics·Yogesh KumarSalman Muzammil

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