High-throughput characterisation of the functional antibody epitope landscape of surface protein targets to guide vaccine and biologic design

Co-supervisor: Prof. Nicole Zitzmann, Department of Biochemistry

Commercial partner: DJS Antibodies

Understanding the nature of antibody-antigen interactions and how these relate to functional outcomes is vital in guiding the rational design of next-generation vaccines and monoclonal antibody (mAb) therapeutics. Whilst many vaccination strategies focus on the induction of broadly neutralising antibodies, Fc-dependent effector functions are increasingly recognised as important in mediating protection against infectious diseases, as well as delivering efficacy for therapeutic mAbs. However, the antigenic targets of such antibodies on cellular surface proteins, and the parameters of the antibody-antigen interaction that relate to functional outcomes are not well understood. This PhD studentship will thus initially focus on a surface protein from the human blood-stage malaria parasite (MSP) that is a known target of complement-fixing inhibitory antibodies. This work will develop novel methodologies for high-throughput mAb isolation, cloning and screening of antibody-antigen interactions that lead to Fc-mediated outcomes – tools that can also easily be applied to human therapeutic mAb targets.

Aims of the PhD project:

i) To develop novel methodologies for the high-throughput isolation of antigen-specific mAbs with rare specificities from human and preclinical samples. To generate MSP-specific human mAbs, this studentship will have access to samples from healthy UK adult malaria challenge studies and from naturally-exposed African adults. Training in and further development of novel high-throughput methodologies to isolate antibodies will be undertaken at Oxford University (antigen-probed based approaches for single cell sorting of memory B cells), and at DJS Antibodies with their proprietary antibody discovery platform.

ii) To interrogate the antibody response and map the antigenic landscape of MSP with a panel of specific mAbs. MAb epitope characterisation will be carried out using state-of-the-art equipment available in the Biochemistry Department, including the Carterra-LSA high-throughput surface plasmon resonance (HT-SPR) platform. Methodologies will be developed in partnership between Oxford and DJS Antibodies that combine HT-SPR screening with novel antigen formats to enable rapid assessment of the diversity of the antibody epitope landscape on a target surface protein.

iii) To develop in vitro functional assays to evaluate the ability of mAbs to engage with complement-mediated and Fc-mediated effector mechanisms to inhibit malaria parasites High-throughput methods to screen for Fc-mediated mAb function against membrane-bound antigens will be established, including antibody-dependent complement fixation (AbC’) and antibody-mediated cellular toxicity (ADCC). These data will be integrated with the epitope landscape information to understand how the nature of surface protein-antibody interactions affects the functional response.

iv) Define key functional epitopes in the MSP for future combination with a neutralising antibody vaccine. The final part of the thesis will explore the ability of multiple antibody effector functions to provide superior growth inhibition against blood-stage malaria parasites.

Overall, this PhD will provide the student with a diverse and high-quality training with a clear translational dimension that spans both academia and industry. This project falls under the UKRI-MRC’s research portfolio of applied global health research, infections and immunity, and molecular and cellular medicine. This  project will also cement a new collaboration between a leading academic laboratory in Oxford and DJS Antibodies, with each partner bringing extensive but unique background expertise.

Apply using course: DPhil in Biochemistry