Background:
The conjugation of polymers such as synthetic poly(ethylene glycol) (PEG) to proteins and drugs intended for therapeutic application is widely used to increase half-life of the protein in the circulation to give a wider therapeutic window. Whilst PEG is the most widely used conjugate and is considered to be biologically inert, repeated administration of PEG conjugates can result in the production of anti-PEG antibodies. In addition, PEG conjugates have been shown to accumulate in tissues, leading to toxicity. Polysialylic acid (PSA), a polymer found almost exclusively on NCAM (neural cell adhesion molecule) has been investigated as an alternative to PEGylation for conjugation to improve the stability and in vivo pharmacokinetics of small drugs and proteins. Advantageously, PSA is a natural polymer and appears to be both biodegradable and non-toxic. In addition, PSA is highly hydrophilic, which results in similar hydration properties to PEG, giving it a high apparent molecular weight in the blood which increases its serum half-life. Since only a small number of human proteins such as NCAM and CD36 scavenger receptor are naturally polysialylated, chemical attachment of PSA to proteins which do not bear natural PSA chains is common. For example, in the case of both insulin and catalase, chemical polysialylation has been shown to improve stability and pharmacokinetic properties whilst preserving normal enzyme function. The commonest site of chemical attachment is via lysine or cysteine amino acid residues of the protein which positions sialylic acid in the reverse orientation to that of naturally occurring PSA. Although polysialylation is being developed as a safer alternative to PEGylation, there is still a requirement to improve the properties of polysialylated proteins.

Invention:
Researchers at a London-based university have developed a method of polysialylation of proteins, whereby sialylation occurs in the natural orientation. The method involves fusing a naturally polysialylated protein, such as NCAM, to the protein of interest and generating a cell line which expresses the fusion protein. In principle, any protein could be expressed in the polysialylated form.

Innovative Aspects:
Benefits:
The conjugation of proteins to polysialylic acid via NCAM fusion proteins has a number of advantages:

- Natural orientation for attachment of PSA offers the potential to further improve stability and immunogenic properties of therapeutic proteins.
- Chemical polysialylation can damage the target protein and lead to a mixture of protein conjugates. In contrast, the method for producing polysialylated-NCAM fusion proteins has the potential to produce a chemically defined and more pharmaceutically acceptable product since polysialylation only occurs at 3 sites on NCAM.
- Recombinant synthesis has the potential to generate higher yields with reduced batch-to-batch variation.

 

Patents/Rights: Patent(s) applied for but not yet granted

Type of Organisation: