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Brief Introduction of Polysialylation Based Half-Life Extension

PSA (polysialic acid) is found on the surface of a variety of cells including mammalian cells, thus is a biocompatible and biodegradable natural polymer, which are highly hydrophilic and has no identified receptors in the body. PSA is a polymer derived from N-ace-tylneuraminic (sialic acid) and has been used for protein conjugation. The hydrophilic nature of PSA is thought to result in similar hydration properties to PEG, giving it a high apparent molecular weight in the blood and therefore increased circulation time. Thus, the posttranslational modification of therapeutic peptides and proteins with terminal sialic acid improves drug pharmacokinetics and reduces immunogenicity, thereby, improving their overall efficiency. To date, PSA, as a promising 'stealth polymer' could be conjugated with protein drugs in vitro by chemical or chemo-enzymatic strategies.

Fig.1 Schemes of polysialic acid use in drug delivery. Long polysialic acids can be used to prolong the circulation time of small drugs and peptides. (Mital, 2000)

Scientists demonstrated that shorter PSA conjugated with an anticancer agent, asparaginase for the treatment of leukemia increased enzyme stability and serum half-life. Another research showed that polysialylated insulin offered a significant enhancement of therapeutic value for the treatment of diabetes. They found that insulin polysialylated with the 22-kDa PSA exerted a more prolonged reduction of blood glucose levels compared to intact insulin treatment in vivo. In addition, the inclusion of a long PSA (e.g. average molecular weight of 60 kDa) greatly prolonged the circulation time of a small model drug, fluorescein which possesses a very short half-life.

Modulation of Antibody Pharmacokinetics by Chemical Polysialylation

Antibodies and their fragments are good examples of the protein types that benefit from pharmacokinetic engineering. In previous research, scientists chemically linked short (11 kDa) and longer (22 kDa) chain colominic acid molecules in different numbers and lengths to Fab fragment of the antitumor monoclonal antibody H17E2. An analysis of the effect of protein polysialylation was investigated using a Fab antibody fragment. The results show that, in all cases, polysialylation generally leads to longer blood clearance times compared to the unmodified Fab, resulting in higher blood exposure and hence greater bioavailability. Increasing the degree of polysialylation 5-fold using the same length polymer chain (22 kDa) led to an almost 2-fold increase in beta-phase blood clearance half-life with little change in antibody affinity. In conclusion, polysialylation can extend the half-life of antibody fragments leading to improved tumor uptake without compromising on the tumor to tissue specificity.

Fig.2 The blood clearance analyses of H17E2 (■) whole IgG and (●) Fab are compared graphically with Fab-PSA conjugates (O) Fab-PSA11, (▽) Fab-PSA22L, and (▼) Fab-PSA22H. (Constantinou, 2008)

Custom Services of Polysialylation Based Half-Life Extension

The prolonged residency of polysialylated conjugates increases the potential of the species to reach its target and provide a therapeutic effect before being cleared from circulation, hence extending the duration of action. Creative Biolabs is an innovative, experienced provider of polysialylation-based half-life extension drug development solutions. We use our state-of-the-art R&D and manufacturing expertise to help our customers develop stand-out products.

If you are interested in our polysialylation-based half-life extension drug development services, please feel free to contact us for more information.

References

1. Mital, M.; McCormack, B. Polysialic acids: potential in improving the stability and pharmacokinetics of proteins and other therapeutics. Cellular and molecular life sciences. 2000, 57(13): 1964-1969.
2. Constantinou, A.; et al. Modulation of antibody pharmacokinetics by chemical polysialylation. Bioconjugate chemistry. 2008, 19(3): 643-650.