Protein therapeutics is indispensable in treating numerous human diseases. Administered protein therapeutics are constantly removed from the human blood requiring frequent administrations. Therefore, extending the protein therapeutics serum half-life will significantly enhance the utility of existing protein therapeutics and will also enable therapeutic development of proteins of which short serum half-life is a big hurdle for clinical applications. In order to extend serum half-life, polyethylene glycol (PEG) has been conjugated to protein therapeutics leading to a reduced elimination in the kidney and an enhanced proteolysis resistance. However, PEG conjugation strategy has several shortcomings. First, random PEG conjugation to multiple sites of protein therapeutics often compromises its biological activity and generates heterogeneous populations requiring complicated purification processes. Second, extension of serum half-life via PEG conjugation is limited to only a certain period of time. Third, it is recently reported that terminal functional groups of the PEG conjugated to protein therapeutics is immunogenic. Therefore, it is imperative to develop alternative strategies to effectively extend serum half-life by overcoming the issues associated with random PEG conjugation. As an alternative to PEG molecule, human proteins are being considered as a biocompatible binding partner to protein therapeutics. In particular, human serum albumin (HSA), the most abundant protein in the human blood, has an extraordinarily long serum half-life. HSA tightly binds to long-chain fatty acids in the blood. We hypothesizes that protein therapeutics conjugated to fatty acids will form the protein therapeutics-HSA complex in the human blood and thereby its serum half-life will be greatly extended. In order to avoid biological activity loss caused by fatty acid conjugation to critical sites of protein therapeutics, we demonstrated that fatty acid can be conjugated to proteins in a site-specific manner using site-specific incorporation of a reactive non-natural amino acid followed by a bio-orthogonal reaction.

Site-specific fatty acid conjugation to proteins for extended serum half-life via albumin binding

245th National Meeting (2013)

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