Engineering Developable Biopharmaceuticals

Summary

The School of Molecular and Cellular Biology invites applications from prospective postgraduate researchers who wish to commence study for a PhD in the academic year 2024/25.

The broad aim of this research is to understand the effects of forces applied onto biopharmaceuticals during their manufacture. Using this knowledge we can then rationally modify either the manufacture process or stabilise the protein sequence to become “manufacturable”.

Biopharmaceuticals, such as monoclonal antibodies, have revolutionised the treatment of diseases with high morbidity and mortality. While it is relatively easy to identify candidate mAbs with high potency and specificity, identifying the subset of candidates that are also stable enough to survive the rigours of large-scale manufacturing is challenging. Over the last 10 years a group of inter-disciplinary researchers at Leeds, comprising experts in protein aggregation (Professor Sheena Radford), high throughput protein engineering (Professor Brockwell) and mechanical engineering (Professor Nik Kapur) have, in collaboration with several leading pharmaceutical companies, designed and applied both in vivo (references 1-3) and in vitro (references 4-6) methods to identify inherently developable biopharmaceuticals. Our group is particularly interested in preventing the intrinsic aggregation of mAb biopharmaceuticals and aggregation triggered by the hydrodynamic forces encountered during manufacture.

In this project you use these assays and other methods to (i) understand the molecular mechanism of manufacture-induced aggregation and (ii) engineer mAbs using rational or directed evolution methods to produce inherently manufacturable biopharmaceuticals.

References

[1] An in vivo platform for identifying inhibitors of protein aggregation. Saunders, J., Young, L., Mahood, R., Jackson, M., Revill, C., Foster, R., Smith, A., Ashcroft, A., Brockwell, D. and Radford, S. (2016) Nat Chem Biol 12: 94–101.
[2] An in vivo platform to select and evolve aggregation-resistant proteins. Ebo J., Saunders J., Devine P., Gordon A., Warwick A., Schiffrin B., Chin S., England E., Button J., Lloyd C., Bond N., Ashcroft A., Radford S., Lowe D. and Brockwell D. (2020) Nat Commun 11:1816.
[3] The effect of mutation on an aggregation-prone protein: An in vivo, in vitro, and in silico analysis. Guthertz N., van der Kant R., Martinez R., Xu Y.,Trinh C., Iorga B., Rousseau F., Schymkowitz J., Brockwell D. and Radford S. (2022) Proc Natl Acad Sci USA 119:e2200468119.
[4] Inducing protein aggregation by extensional flow. Dobson, J., Kumar, A., Willis, L., Tuma, R., R. Higazi, D., Turner, R., Lowe, D., Ashcroft, A., Radford, S., Kapur, N. and Brockwell, D. (2017) Proc Natl Acad Sci USA. 114:4673-4678.
[5] Using extensional flow to reveal diverse aggregation landscapes for three IgG1 molecules.Willis L., Kumar A., Dobson J., Bond, N., Lowe D., Turner R., Radford S., Kapur N. and Brockwell D. (2018) Biotech Bioeng 115:1216-1225.
[6] The uniqueness of flow in probing the aggregation behavior of clinically relevant antibodies. Willis L., Kumar A., Jain T., Caffry I., Xu Y., Radford S., Kapur N., Vasquez M. and Brockwell D. (2020) Eng Rep 2:e12147.

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.