Abstract
Clinical applications of technological proteins has been limited because of their rapid clearance from the blood, due to glomerular filtration, proteolysis, hepatic uptake and immunogenicity. In recent years, chemical modifications of proteins with water-soluble polymers typified by polyethylene glycol (PEG) have been found to effectively overcome these drawbacks. For instance, PEG-modified proteins have been proven to have increased plasma half-lives and stability, and reduced immunogenicity in vivo. These effects are attributed to an increased molecular weight and steric hindrance, both of which are derived from PEG attached to proteins. However, clinical application of modified proteins has been limited yet. This is due to the conflicting effects of chemical modification of proteins ; modified proteins limited the transport from blood to tissues due to the high molecular weight, and sterically inhibited the binding to their receptor, resulting in loss of bioactivity. Nevertheless, an optimal modification-condition, which is a well-balanced tissue transport, receptor-binding, and plasma clearance, must be in existence. For the molecular design of modified proteins applicable to clinical use, the discovery of the optimal modification-condition, which is dominated by the steric hindrance and molecular weight, should be a primary concern. In this review, we indicated that the optimal modification of biological-active protein, such as TNFα, with water-soluble polymer markedly increased its bioavailability and was also reduced its toxic side-effects. This review will provide a fundamental information enabling us to design the modified proteins applicable to therapeutic use.
