Monoclonal antibodies can target immune checkpoints to deliver novel therapies for cancer. In this PhD you will study immunostimulatory antibodies targeting the Tumour Necrosis Factor receptor superfamily that are capable of activating immune cells to deliver enhanced T cell priming, expansion, secretion of inflammatory cytokines and tumour cell killing. Our targets include the receptors CD40, OX40 and 4-1BB.
The particular strength of the host laboratory is the generation of monoclonal antibodies that work in an Fc receptor independent manner to deliver agonism. To understand the underlying molecular mechanisms, the PhD will employ a combination of bio-chemical and -physical, structural and computational methods. By combining these, you will seek to understand the relationship between key properties such as epitope, affinity as well as antibody hinge-flexibility for immunostimulatory activity. The knowledge gained will be used to generate new antibodies for clinical testing, which extends the benefit of immunotherapy to more people with cancer.
Several published and unpublished X-ray structures serve as a starting point for targeting the mAb:receptor interface in a directed, structure-based approach. Biochemical characterisation of variants and crystallographic structures will guide this approach. The changes in antibody structure conformation and dynamics are addressed with Small Angle X-ray Scattering studies (SAXS) and full atomistic MD simulation with enhanced sampling approaches, such as metadynamics. The PhD thus offers a unique combination of experiment and molecular simulation to rationalise, at the molecular level, the fundamental mechanisms underpinning immunostimulatory activity.
Candidates will have strength in one (or more) or the following: computational chemistry; structural biology; immunology. You will be placed in a highly interdisciplinary environment and be given the opportunity to learn the relevant skills for this project and interact with experts in the field. Embedded within Computational Chemistry with access to High Performance Computing on IRIDIS5, the biophysical and structural environment at Institute for Life Sciences, and the translational immunology remit at the Centre of Cancer Immunology, the PhD provides a truly comprehensive interdisciplinary cross-campus experience. The PhD will lay a solid foundation for a future carrier in either academia or industry.
References: Mol Immunol. 83 (2017), 13-22; Cancer Cell. 33 (2019), 664-675; Biophysical Journal. 115 (2018), 289-299; Cancer Cell. 37 (2020), 850-866, JCI Insight 5 (2020), e141593.
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