Project overview
Background: The last decade has seen an explosion in antibody therapeutics, with over 100 now approved for use in multiple cancer types. Despite this success, these treatments fail to elicit durable responses in all patients, can be toxic and subject to resistance mechanisms. Understanding these resistance mechanisms and developing strategies to overcome them is critical to developing the next generation of more effective anti-cancer antibodies. We, and others, have shown that their activity is modulated through interaction with Fc gamma receptors (FcgR). In the last 5 years we have revealed that myeloid cells and particularly macrophages are key determinants of antibody efficacy with tumour specific factors and microenvironmental elements, such as hypoxia, modulating their FcgR expression patterns and reducing anti-tumour activity. These effects are achieved in part through polarising the macrophages to suppressive states, modulating expression of multiple cell surface receptors. These receptors are typically associated with poor progression free survival in multiple cancer types and so represent attractive targets. By targeting these receptors with next-generation antibody strategies we hypothesise that we can modulate the activity and composition of the myeloid/macrophage cells in the tumour to improve antibody immunotherapy. Aims: 1) Determine genomic, transcriptional and spatial relationships underpinning FcgR and myeloid receptor expression patterns in tumours 2) Generate new antibodies and establish how FcgR interactions impact antibody targeting of different classes of myeloid receptor 3) Evaluate antibody safety and efficacy Methods: The programme benefits from interactions between experts in antibody engineering, receptor biology, macrophages and tumour microenvironment. Using a combination of single cell and spatial transcriptomics techniques alongside confirmatory protein approaches (flow cytometry and multiplex IHC), we will reveal key associations between myeloid receptor expression and the tumour architecture. Subsequently, we will generate antibody molecules designed to exploit the receptor and FcgR expression patterns observed, employing novel engineering approaches. Finally, a unique panel of transgenic and humanised mouse models, alongside human tissue systems will allow appropriate evaluation of our new antibody therapeutics with regards efficacy and toxicity. How the results of this research will be used: This programme will generate deeper mechanistic understanding of how myeloid cells are regulated in tumours, how they can be manipulated with antibodies targeting their surface receptors and reveal the principles that determine toxicity versus therapeutic efficacy. We will apply this knowledge to generate new antibodies and formats for clinical testing that could extend the benefit of antibody immunotherapy to more people with cancer.
