Research

Jasmine Bickel

Novel adjuvants for antibody-based cancer therapeutics: design, biological characterization and influence on membrane-protein structure

Jasmine Bickel - 3rd year PhD

Abstract

Monoclonal antibodies (mAbs) are one of the most exciting new classes of anticancer agent, with a current market of over $20 billion forecast to grow by 50% in the next 3 years. The mechanism by which mAbs kill cancer cells during cancer immunotherapy treatments is complex, and involves the interplay of multiple effectors, including selective activation of complement-dependent cytotoxicity (CDC). Membrane attack complex (MAC) pores contribute to CDC, and are counteracted by membrane-bound complement inhibitors such as CD59, which are overexpressed on tumor cells and can provide a mechanism for immune evasion. Interestingly, bacterial pore-forming toxins with a similar structural fold to MAC proteins (e.g. Streptococcus Intermedilysin, ILY) compete for CD59-binding through a specific interface, and increase cells’ susceptibility to CDC. This project will integrate a platform of technologies to determine how MAC pores lyse cells and how CD59 regulates this process, providing fundamental insights into the mechanism of action of rituximab. This platform will be exploited to design and optimize compounds that can specifically block CD59, and thus potentiate anticancer immunotherapy.