For Research Use Only. Not for Clinical Use.

Overview of HESylation Based Half-Life Extension

A modified form of plant polysaccharide amylopectin is Hydroxyethyl starch (HES) which is a natural polymer. Hydroxyethylation makes the polysaccharide more water-soluble and prevents degradation due to a-amylase. The conjugation of HES moieties increases the hydrodynamic volume of the modified molecule, thereby making it less clearance susceptible to renal. HESylation, as the name suggests, involves the covalent coupling of HES to the molecule of interest. HES is characterized by a combination of desirable properties like excellent biocompatibility, tunable biodegradability, and high tolerable doses. As a result, HESylation for half-life extension represents a promising alternative to PEGylation technology. HESylation technology showed promising success in the half-life extension of protein therapeutics including erythropoietin and FVIII.

Fig.1 Examples of HESylation chemistry. (van Witteloostuijn, 2016)

Chemical Options of HESylation

• Random HESylation
  Early results for HESylated proteins such as hemoglobin were obtained by a random conjugation step. However, these HES conjugates faced some manufacturing limitations and suffered from toxicity problems. As with PEGylation, random HES linkage resulted in conjugation to a number of lysine residues with poorly controllable stoichiometry. The tolerance of such conjugates was quite low in animal experiments due to the high fraction of covalently linked high molecular weight aggregates.
• Site-Specific HESylation
  Site-directed HESylation was applied to several low molecular weight substances like amphotericin B, peptides, and proteins such as an erythropoietin mimetic peptide, erythropoietin, and interferon α-2b. In vivo studies in dogs performed for such conjugates showed that half-life can be tuned by varying the molar mass (MW) and molar substitution (MS). The HES conjugate with high MW and high MS led to a threefold longer half-life compared to that of the commercially available glycosylated form.

Custom Services of HESylation Based Half-Life Extension

Creative Biolabs has focused on the half-life extension drug development for many years. We have a very professional technical team and rich project experience in HESylation-based half-life extension drug development. If you have any problems with half-life extension drug development or you are interested in our services, please do not hesitate to contact us for more details.

Reference

1. van Witteloostuijn, S.B.; et al. Half-life extension of biopharmaceuticals using chemical methods: alternatives to PEGylation. ChemMedChem. 2016, 11(22): 2474-2495.