Improving Safety and Efficacy of Protein Therapeutics by Chemical Modifications
MetadataShow full item record
Protein therapeutics offer the advantages of high specificity and potency. However, their applications are greatly limited due to undesired immune responses, which not only reduce their therapeutic efficacy, but also cause many adverse effects including anaphylaxis and infusion reactions. Although several PEGylated protein drugs were brought into clinic, they are still vulnerable to anti-PEG antibodies. In this dissertation, tactics to improve the efficacy and safety of protein therapeutics are discussed. Learning lessons from PEGylation, a zwitterionic gel encapsulation technology is developed to protect protein drugs from body clearance and immune recognition. This strategy is proved to be effective in increasing protein stability, prolonging in vivo circulation half-life and reducing immunogenicity, and is successfully applied to uricase, butyrylcholinesterase (BChE) and organophosphate hydrolase (OPH) for both therapeutic and protective applications. In addition, several new capabilities have also been developed in the course of this work. First, to reduce current PEG related clinical risks, a surface plasmon resonance biosensor is applied to detect anti-PEG antibodies quantitatively with better sensitivity than direct ELISA. Second, to solve potential organ accumulation and associated toxicity problems, a carboxybetaine group functionalized polypeptide is synthesized to introduce biodegradability to the protein modification material. Third, to handle highly immunogenic therapeutics, an immunomodulatory bioconjugation is developed to proactively suppress anti-drug antibodies. These new technologies have the potential to improve the pharmacokinetics and immunogenicity of currently marketed biopharmaceutics, and unlock the possibility of adopting highly immunogenic proteins to improve human health.
- Chemical engineering