Controlling protein self-assembly and stability using biological ions

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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 interdisciplinary project combines expertise in physicochemical sciences and biosciences for delivering more effective treatments that improve patient health and well-being. Because the biopharmaceutical sector has predominantly used a limited number of approved excipients, much room for innovation exists. Here, we explore exploiting the ways cells have naturally evolved to maintain the stability of densely-packed macromolecular environments, which relies, in part, on small multivalent ions, a good example being nucleotides. If successful, the technology could be rapidly translated into industry thereby demonstrating economic and societal impact. It builds upon expertise of leading academic groups and an innovative biotechnology company and combines state of the art analytical capabilities for advancing the reputation and leadership in UK formulation science. There exists a gap in well-trained bioformulation scientists, which will be addressed through training that crosses boundaries between engineering and life sciences combined with hands-on experience at a thriving biopharmaceutical facility.