Protein Conjugation - Lessons Already Learned in the Diagnostics Sector

Conjugated protein drugs have received an ever-increasing level of interest in the past few years, but so far there appears to have been little recognition within the pharma sector that there is a large body of knowledge whose application could pay big dividends for drug developers.

Multiple advantages of conjugated biopharmaceuticals

The potential advantages offered by conjugated biopharmaceuticals as a category are manifold:

• the classic 'magic bullet' approach first advanced by Paul Ehrlich in about 1900 requires a single entity to combine the desired therapeutic properties with the ability to localise at the desired target. Examples where these two properties are found within a single protein molecule are very rare - but by coupling a (protein or non-protein) therapeutic entity to a targeting protein such as an antibody, this combination of properties can readily be achieved.
• conjugation techniques such as PEGylation with polyethylene glycol have long been recognised as useful tools for modifying in vivo drug properties with respect to biotransport properties, clearance rates, and so on.
• the conjugation of multiple therapeutic protein 'copies' to a carrier backbone can offer the potential of significant amplification over the performance of a protein monomer.

However, at a more detailed level, the impact that the exact nature of the conjugation chemistry can have on biopharmaceutical performance is not as clearly recognised within the sector as might be expected. Different coupling agents have different properties with respect to key pharmaceutical parameters such as immunogenicity and bioavailability of the conjugate components. Controllable variables such as reaction ratios and conditions and purification methods would be expected to have a significant impact too. There are many techniques available for the optimisation of conjugate performance to 'tune' conjugate performance, reasonably well-known in the diagnostics sector but considerably less so in the pharma field.

Similarly, such factors can have a major impact on process yield and robustness - so the impact goes beyond drug performance per se to economic and manufacturability issues. Even during the development phase, factors such as efficient use of scarce protein resources can be an important time-to-market issue.

Finally, the ability of a conjugate to be sufficiently characterisable to be acceptable to regulatory authorities is strongly dependent on the chemistry employed - another key factor in the route to market.

Given the lack of knowledge in this speciality within the pharmaceutical sector, it is undoubtedly the case that good drugs are 'sitting out there' undiscovered because insufficient effort has been applied to optimisation of conjugation procedures. World-class diagnostic manufacturers do not expect to achieve exquisite assay sensitivity without putting the appropriate level of effort into conjugate optimisation - and the same principle applies, possibly even more strongly, to the development of marketable biopharmaceuticals.

Since the launch of the anti-leukemia agent Myelotarg, which gained FDA approval in 2000, targeted protein drugs have become a reality, and all the evidence suggests that conjugated proteins are being increasingly recognised as exciting development targets. Service providers in this field are now seeing this category representing 10-20 per cent of their biopharmaceutical workload, and probably the majority of biopharmaceutical executives interviewed in the past 12 months have plans for such products in their development portfolio. A deep knowledge base will be essential in maximising the potential of this drug category - it will not be achieved by following standard generic methods or by buying off-the-shelf conjugation kits.

Protein conjugation chemistry has the potential to offer an exciting new wave of biopharmaceutical candidates, and that - provided the appropriate effort is put into rational method development - these will be transformed into successful drugs.

Author: Alistair Dent

This article is a precis of a feature on Protein Conjugation and Fleet Bioprocessing which appeared in the April edition of SP2 Magazine. To download a .pdf copy of the article, click here.

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