Advances and challenges in developing cytokine fusion proteins as improved therapeutics

Abstract

Background: Recombinant forms of natural proteins with therapeutic potential rarely make ideal pharmaceuticals. Fusion of these proteins to human serum albumin, human transferrin, the constant region fragment of a human IgG or a desirable antibody to improve their bioavailability, reduce unwanted side effects and confer targeting specificity has been an important area of research. Some of these fusion proteins have been in clinical trials to assess their safety and efficacy. Objective/method: This review summarizes the drug discovery/development efforts of select cytokine fusion proteins as improved therapeutics, with a particular focus on cytokines fused to tumor-targeting antibodies for treating cancers. In addition, the application of the modular Dock-and-Lock method as a tool to generate multimeric cytokines linked to an antibody of interest is introduced, and the challenges to overcome the deficiencies noted in the current generation of cytokine fusion proteins are discussed. Key literature on fusion or conjugation of cytokines to various carrier proteins published since 1988 was reviewed. Conclusion: To achieve the full promises of cytokine fusion proteins, it is imperative to focus further development on improving pharmacokinetics and in vivo stability, as well as minimizing potential immunogenicity and inherent toxicity.

Keywords::

• Dock-and-Lock
• fusion proteins
• monoclonal antibodies
• multimeric cytokines