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(BBRSC DTP CASE) Controlling interfacial adsorption of bispecific therapeutics using multivalent ions


Project Description

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. A key issue is linked to their propensity for adsorbing to plastic surfaces. Because the molecules are administered to patients at low concentrations, any surface adsorption to IV bags or syringes leads to poor control over their intended dose. Current methods for prevention require using surface-active ingredients, such as non-ionic surfactants or albumin, which adsorb to hydrophobic substrates thereby forming a surface layer that protects against further adsorption of proteins. This translates into a complex dose preparation regime in the clinic. However, very little is known about how other accessible excipients for formulation development modulate protein interfacial behaviour.

The overall aim of this study is to investigate whether multi-valent ionic excipients can be used to tune the adsorption behaviour of ImmTAC molecules to plastic substrates. Previous work has already shown that binding of multi-valent ions, such as adenosine tri-poly phosphate (ATP), to proteins prevents their thermal induced aggregation by increase colloidal stability through a super-charging mechanism. Further, electrostatic interactions play an important role in protein adsorption to solid substrates, either through direct protein-surface interactions, or indirectly, in terms of lateral interactions that occur between adsorbed proteins. Along these lines, a recent study has shown that trivalent cations prevent surface buildup of a negatively charged protein due to an over-charging effect.

The project will involve a broad range of experimental methodologies, ranging from a screening protocol for monitoring protein losses due to surface adsorption, biophysical measurements of protein solution behaviour using light scattering, spectroscopic, and chromatographic approaches, and state of the art characterization tools for monitoring surface properties of plastics and the protein adsorbed layers on model substrates.

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:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

• Bye and Curtis (2019) “Controlling phase separation of lysozyme with polyvalent anions”, J. Phys. Chem. B v23: 593.
• Patel et al., (2017) “ATP as a biological hydrotrope”, Science v356: 753.
• Attwood et al. (2019) “Understanding how charge and hydrophobicity influence globular protein adsorption to alkanethiol and material surfaces”, J. Materials Chem. B v7: 2349.
• McNamara and Blanford (2016) “A sensitivity metric and software to guide the analysis of soft films measured by a quartz crystal microbalance”, Analyst v141: 2911.

How good is research at The University of Manchester in Aeronautical, Mechanical, Chemical and Manufacturing Engineering?
Chemical Engineering

FTE Category A staff submitted: 33.90

Research output data provided by the Research Excellence Framework (REF)

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