Notes

Medicine -- Therapeutic Proteins and Polypeptides

1. What do you know about the clinical importance of therapeutic proteins/peptides?

Therapeutic proteins/peptides are organic macromolecules which the body recognises. Hence, the body is less likely to reject these proteins unlike other foreign drugs where anti-drug antibodies may be produced by the body. They are also highly specific and results in decreased drug toxicity (minimal interference with other body processes). They serve as an alternative for gene therapy (which has a high margin for error like mutated genes and raises many ethical concerns)

They are commonly used to treat neurodegenerative disorders like Alzhemier’s disease and certain cancers like leukaemia. Therapeutic proteins are also found to be highly effective in vivo, which make them suitable for use in humans.

Therapeutic proteins can be used in many ways through the development of recombinant DNA technology. They can replace defective proteins in the body, provide new functions or activities, upregulate certain pathways (proteins with enzymatic properties). They can also deliver other substances (E.g. cytotoxic drugs) to combat diseases (proteins with specialised targeting properties) and can even serve as vaccines.

2. What do you think are the bottleneck in the processing of these therapeutic proteins/peptides?

Firstly, various types of chromatography and filtration methods used to purify therapeutic proteins can create conditions which increase the risk of protein aggregation which may be irreversible and insoluble. (E.g. change in Ph values, strong hydrophobic interactions, protein unfolding, etc). This aggregation may then result in increased immunogenicity, where the body produces anti-drug antibodies to destroy the aggregate.

Predicting and eliminating aggregation prone regions may can reduce the chances of aggregation. However, changing the bonding arrangements of the protein may give rise to neoepitopes which are even easier to detect by the immune system’s helper T-cell, resulting in immunogenicity still being increased.

Secondly, there is the problem of therapeutic proteins having a sub-optimal duration of action and/or circulation half-life. If circulation is too short, frequent administration is required. This results in dose dumping which causes a subtherapeutic effect after each new administration of therapeutic proteins. If circulation is too long, possible protein instability and toxicity issues may arise.

PEGylation is a commonly used method to increase the half-life of proteins. However, studies show that overexposure to PEGylated proteins and products that contain PEG (E.g. skin care) can cause an immune response where the body develops anti-PEG properties even though PEG is weakly immunogenic. Furthermore, PEG can also reduce the binding affinity of a protein, which reduces its physiological response to ligands and thus is less efficient.