Controlling the quality of novel glycoprotein therapeutics

Candidates should hold or be near completion of a Masters-level degree in Life Sciences or Chemical/Biochemical Engineering.

Start sate: October 2015

Project description

Therapeutic glycoproteins represent 40% of biologics currently approved by the European Medicines Agency. With specific productivities in biotechnological processes estimated to reach their theoretical maximum in the near future, and despite anticipated further increases in culture density, the scope for improvement of biotherapeutics is limited in terms of production volume. As a result, there is an increased focus on biotherapeutic efficacy in both the development and production stages. Modification of the glycoform can enhance efficacy, mode of action and half-life and thus is a target for drug design. Simultaneously, N-glycosylation plays a key role in the safety of biotherapeutics, since certain glycan structures have been found to trigger undesired effects in patients. Therefore, N-linked glycosylation a key quality control target both from the therapeutic efficacy and safety standpoints. A well-defined product may have consistent protein backbones but still a glycoform distribution of more than a hundred detectable isoforms.

There is a large volume of evidence that process conditions affect N-linked glycosylation. Lack of carbon availability directly affects the intracellular availability of nucleotide sugars, the co-substrates of glycosylation, without which the glycan processing in the Golgi cannot continue. Other studies have shown that high ammonia concentrations and extremes of pH lead to poor glycoprofiles. Our own research on monoclonal antibody (mAb)-producing cell lines has shown that the glycoprofile also depends on the culture temperature.
Non-antibody products, such as therapeutic enzymes, certain fusion proteins and other established proteins (e.g. erythropoietin and its biosimilars) are gaining an increasing share of the biotherapeutics market. Their glycosylation motifs are typically more complex than those of mAbs since the glycan chain is not limited by steric hindrance. The higher complexity leads to more potential for variation, making them a manufacturing challenge. We will systematically investigate cell culture systems producing non-mAb glycoproteins and identify process control parameters that can be manipulated to yield the desired glycoform to a high degree of homogeneity. The research will rely on a novel mathematical model that links bioprocess conditions to protein glycosylation. The model will act as a platform for the design of experiments for validation for new cell line/products and sensitivity analysis to pinpoint appropriate process controls. It will further be used for bioprocess design and optimisation to narrow the glycomic profile of the recombinant product.

To apply and for more information please contact Dr Cleo Kontoravdi: [Email Address Removed]

Full funding is available to all U.K. Citizens and EU nationals who have resided in the U.K for at least 3 years before the start of the Ph.D.

http://www.imperial.ac.uk/people/cleo.kontoravdi98