Development of Novel DDS Technologies for Optimized Protein Therapy by Creating Functional Mutant Proteins with Antagonistic Activity

Abstract

  In the post-genomic era, cytokine or antibody therapy has received attention for advanced drug therapies. Indeed, attempts are being made to develop a wide variety of therapeutic proteins for diseases including cancer, hepatitis and autoimmune conditions. Unfortunately, however, the utilization of bioactive proteins in clinical practice is often limited because of their inherent instability and pleiotropic actions in vivo. Our laboratory aims to overcome two major problems, details of which will be addressed in separate sections to follow. (i) Development of a powerful system to rapidly create functional mutant proteins (muteins) with enhanced receptor affinity and receptor specificity using a phage display technique (biological DDS). (ii) Establishment of a novel polymer-conjugation system to dramatically improve in vivo stability and selectively of bioactive proteins (polymeric DDS). We are currently attempting to combine both approaches to create a protein-drug innovation system to further promote pharmaco-proteomic-based drug development. In this review, we will describe DDS-based technology for creating functional mutants for advanced medical applications, using tumor necrosis factor-alpha (TNF) as an example.