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The Dilemma of Biopharmaceuticals

Most biopharmaceuticals are based on endogenous peptides and proteins, such as hormones, enzymes, growth factors, interferons, and antibodies. Inherently, these natural ligands possess superior drug properties such as highly selective receptor binding and potent receptor activation. Most of these recombinant proteins are identical or similar to the natural protein and thus exhibit similar pharmacokinetic (PK) properties to their natural counterparts. A comparison of half-lives of these therapeutic proteins, often possessing a molecular mass below 50 kDa, shows that most of them exhibit terminal half-lives below 1 day, many in the range of minutes to a few hours, and thus are rather rapidly cleared from circulation. There are only a few exceptions, including IgG molecules, which can have exceptionally long half-lives of up to 4 weeks. This challenge has prompted the development of several half-life extension strategies to improve the PK properties of native peptides and proteins.

Fig. 1 Factors that limit residence time of protein in circulation and a few ways to address them. (Zaman, 2019)

Importance and Strategies of Half-life Extension in Drug Development

Why do we need half-life extension and what are the most prominent half-life extension strategies? Many of the approved biotherapeutics are used for replacement therapy, substituting a deficient or defective protein. Often, the natural protein is produced in the human body to maintain a more or less constant level or is produced or released after stimulation, e.g. by metabolic changes. Because of a rapid clearance, frequent applications of a therapeutic protein are required to achieve and maintain effective concentrations over the desired period. Extending the plasma half-life can help extend the time between applications and thus reduce patient burden and improve quality of life, especially in cases of chronic diseases requiring lifelong treatment. This has been recognized by the pharmaceutical industry and meanwhile, approximately 15% of the approved therapeutic proteins are modified for half-life extension. Most of the half-life extended recombinant biotherapeutics are PEGylated proteins followed by fatty acid modifications mediating binding to serum albumin. Furthermore, novel biotherapeutics have been developed fusing a therapeutically active protein, such as a coagulation factor or ligand-binding receptor fragment acting as a trap, to an Fc part. Other modifications include the direct fusion to serum albumin, as utilized for glucagon-like peptide-1 (GLP-1), and glycoengineering as in the case of erythropoietin.

Fig. 2 Protein half-life extension techniques at a glance. (Zaman, 2019)

Custom Services of Half-Life Extension Drug Development 

References

1. Zaman, R.; et al. Current strategies in extending half-lives of therapeutic proteins. J Control Release. 2019, 301: 176-189.
2. van Witteloostuijn, S. B.; et al. Half-Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation. ChemMedChem. 2016, 11(22): 2474-2495.

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