About the Project
Therapeutic monoclonal antibodies (MAbs) targeting B cell surface antigens have revolutionised treatment of autoimmune diseases including rheumatoid arthritis, neurological disorders such as multiple sclerosis, and B cell malignancies including lymphoma and chronic lymphocytic leukaemia. CD20 antibodies, such as rituximab, obinutuzumab and ofatumumab have delivered major improvements in patient outcomes.
Despite this success, both the physiological function of CD20 and the precise mechanisms of action of CD20 MAbs remain incompletely understood. CD20 MAbs are pleiotropic and can induce antibody dependent cellular cytotoxicity, activate complement, induce apoptosis and cell cycle arrest, B cell polarisation and homotypic cellular aggregation. Which of these mechanisms are critical for B cell depletion in vivo remains uncertain.
We have observed that some therapeutic MAbs induce a novel form of in vitro B-cell depletion. B cells labelled with specific MAbs are depleted on passing through the fluidics of flow cytometers. This process is rapid (occurring in <15mins), dependent on the precise epitope recognised by the MAb, antigen density, on temperature and the presence of divalent metal ions, and is not suppressed by inhibitors of forms of programmed cell death.
Our hypothesis is that some MAbs rapidly induce changes at the lymphocyte plasma membrane resulting in cell lysis under conditions of fluidic stress; the biological basis of this mechanism is unknown.
We propose a series of detailed biophysical investigations to study the consequences of antigen/antibody interactions at the cell surface membrane of well-characterised B cell lines.
In particular, the research will take advantage of new transformative technology for single molecule force measurements – an apparatus called the Lumicks C Trap which combines optical-force tweezers with microfluidics and confocal imaging. Additional imaging modalities will include atomic force and cryo-electron microscopy.
Techniques that will be undertaken during the project
- Cell culture
- Biophysical binding assays
- Single-molecule force spectroscopy
- Western blot
- Fluorescence microscopy
- Cryo-electron microscopy
Enquiries
Project Enquiries to [contact details available in the full listing]
Programme enquiries to [contact details available in the full listing]
To apply please refer to
https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp
Funding Notes
All MIBTP students will be provided with a 4 year studentship. This includes: Tuition fees at the UK fee rate*, a tax free stipend which for 2026/7 is £21,805 per year (2027/8 stipend to be confirmed), a travel allowance over years 1-3, a travel/conference budget, a generous consumables budget, use of a laptop for the duration of the programme. The University of Leicester will provide full overseas fee waivers for the duration of their study to all international students accepted at Leicester. The funder, UKRI, allows us to appoint up to 30% overseas students.
