Peptides and proteins are two classes of molecules with attractive possibilities for therapeutic applications.
However, the bottleneck for the therapeutic application of many peptides and proteins is their short halflives
in vivo, typically just a few minutes to hours. Half-life extension strategies have been extensively studied
and many of them have been proven to be effective in the generation of long-acting therapeutics with improved
pharmacokinetic and pharmacodynamic properties. In this review, we summarize the recent advances in half-life
extension strategies, illustrate their potential applications and give some examples, highlighting the strategies that
have been used in approved drugs and for drugs in clinical trials. Meanwhile, several novel strategies that are still
in the process of discovery or at a preclinical stage are also introduced. In these strategies, the two most frequently
used half-life extension methods are the reduction in the rate of renal clearance or the exploitation of the
recycling mechanism of FcRn by binding to the albumin or IgG-Fc. Here, we discuss half-life extension strategies
of recombinant therapeutic protein via genetic fusion, rather than chemical conjugation such as PEGylation. With
the rapid development of genetic engineering and protein engineering, novel strategies for half-life extension
have been emerged consistently. Some of these will be evaluated in clinical trials and may become viable alternatives
to current strategies for making next-generation biodrugs.
Glucagon-like peptide-1 (GLP-1) is considered to be a promising peptide for the treatment of type 2 diabetes mellitus (T2DM). However, the extremely short half-life of GLP-1 limits its clinical application. Albumin-binding domain (ABD) with high affinity for human serum albumin (HSA) has been used widely for half-life extension of therapeutic peptides and proteins. In the present study, novel GLP-1 receptor agonists were designed by genetic fusion of GLP-1 to three kinds of ABDs with different affinities for HSA: GA3, ABD035 and ABDCon. The bioactivities and half-lives of ABD-fusion GLP-1 proteins with different types and lengths of linkers were investigated in vitro and in vivo. The results demonstrated that ABD-fusion GLP-1 proteins could bind to HSA with high affinity. The blood glucose-lowering effect of GLP-1 was significantly improved and sustained by fusion to ABD. Meanwhile, the fusion proteins significantly inhibited food intake, which was beneficial for T2DM and obesity treatment. The half-life of GLP-1 was substantially extended by virtue of ABD. The in vivo results also showed that a longer linker inserted between GLP-1 and ABD resulted in a higher blood glucose-lowering effect. The fusion proteins generated by fusion of GLP-1 to GA3, ABD035 and ABDCon exhibited similar bioactivities and pharmacokinetics in vivo. These findings demonstrate that ABD-fusion GLP-1 proteins retain the bioactivities of natural GLP-1 and can be further developed for T2DM treatment and weight loss. It also indicates that the ABD-fusion strategy can be generally applicable to any peptide or protein, to improve pharmacodynamic and pharmacokinetic properties.
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