(BBSRC DTP CASE) Controlling interfacial adsorption of bispecific therapeutics using biological hydroptropes

ImmTAC molecules are a promising new class of bispecific therapeutics produced by Immunocore for applications in oncology and as new treatments for infectious diseases. They are fusions of a T cell receptor (TCR) and a scFv antibody fragment with anti-CD3 effector function. As with most next-generation therapeutics, ImmTACC molecules are difficult to manufacture due to poor stability, high aggregation levels, and adsorption to surfaces. In particular, as ImmTACC molecules are administered at low concentrations, any surface adsorption to IV bags or syringes leads to poor control over their intended dose. Once a therapeutic is in development, the main route for controlling stability is through adding excipients. Current approaches, however, are not satisfactory and there is an urgent need for novel, but biologically safe excipients. One unexplored area involves mimicking how cells prevent non-specific protein aggregation through the use of biological hydrotropes. For example, ATP is proposed to not only function as an energy source, but also to maintain protein solubility in vivo. In this project, we will explore using biological molecules as stabilization agents in formulations. The work aims to gain a mechanistic understanding from elucidating and measuring the underlying bio-molecular interactions. While a key outcome is to stabilize therapeutics, we will gain insights about how cells maintain stability of densely packed protein environments and the formation of membraneless organelles, which is driven by subtle changes to protein solubility.

The project will involve a broad range of experimental methodologies, ranging from biophysical measurements of protein solution behaviour and intermolecular interactions using light scattering, spectroscopic, and chromatographic approaches, and state of the art characterization tools for monitoring biomolecular surface interactions and the structures of protein adsorbed layers on model substrates. Training in these experimental methodologies is especially relevant for research and development of any biopharmaceuticals including gene therapies.

Industrial Partner: https://www.immunocore.com/
Robin Curtis: https://www.research.manchester.ac.uk/portal/r.curtis.html
Alain Pluen: https://www.research.manchester.ac.uk/portal/alain.pluen.html
Christopher Blanford: https://www.research.manchester.ac.uk/portal/christopher.blanford.html

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/