Dr William Kelton
Annmaree Warrender (In progress): "The hidden influence of antibody polymorphism"
Our research focuses on using new tools to manipulate and investigate proteins that are involved with mammalian immune responses. We blend aspects of molecular biology, immunology, and protein engineering to better understand how we can improve important protein drugs such as antibodies. We are also aiming to understand the effect these molecules exert when they interact with other elements of the immune system.
Investigating the Immune Influence of Natural Antibody Diversity
It has long been known that antibodies have massive diversity in their variable regions, this allows the immune system a high degree of flexibility to produce antibodies that can counter new immune threats. Lesser known and poorly understood is diversity in the constant region of antibodies. As this constant region directs cell-mediated immune responses, we are seeking to determine how this diversity influences our internal fight against infection and disease.
Protein Engineering to Enhance Antibody Immune Function
Antibodies are widely used as therapeutic drugs in cancer treatments and to prevent infectious disease. With our collaborators at ETH Zurich, we are using CRISPR/Cas9 to modify the sequence of antibodies in mammalian cells and create libraries of antibody variants. We can then screen these libraries to look for enhanced antibody function which is mediated by binding to Fc receptors. Antibodies with enhanced effector function are potential candidates for cancer therapy.
Characterisation of Antibody Isotypes
Most clinically explored antibodies are of the IgG isotype and have exceptionally potent action and long residence times in circulation. Lesser explored are antibodies of the IgA and IgE subclasses. We are interested in investigating the therapeutic power of these antibody subclasses for applications in mucosal immunity and in allergy.
Research Publications by Will Kelton
Pogson, M., Parola, C., Kelton, W.J., Heuberger, P. and Reddy, S.T., 2016. Immunogenomic engineering of a plug-and-(dis) play hybridoma platform. Nature communications, 7(1), pp.1-10.
Mason, D.M., Weber, C.R., Parola, C., Meng, S.M., Greiff, V., Kelton, W.J. and Reddy, S.T., 2018. High-throughput antibody engineering in mammalian cells by CRISPR/Cas9-mediated homology-directed mutagenesis. Nucleic acids research, 46(14), pp.7436-7449.
Kelton, W.J., Pesch, T., Matile, S. and Reddy, S.T., 2016. Surveying the delivery methods of CRISPR/Cas9 for ex vivo mammalian cell engineering. CHIMIA International Journal for Chemistry, 70(6), pp.439-442.
Kelton, W., Waindok, A.C., Pesch, T., Pogson, M., Ford, K., Parola, C. and Reddy, S.T., 2017. Reprogramming MHC specificity by CRISPR-Cas9-assisted cassette exchange. Scientific reports, 7, p.45775.
Warrender, A. K., & Kelton, W. (2020). Beyond allotypes: The influence of allelic diversity in antibody constant domains. Frontiers in Immunology, 11. doi:10.3389/fimmu.2020.02016 Open Access version: https://hdl.handle.net/10289/13745
Pesch, T., Bonati, L., Kelton, W., Parola, C., Ehling, R. A., Csepregi, L., . . . Reddy, S. T. (2019). Molecular design, optimization, and genomic integration of chimeric B cell receptors in murine B cells. Frontiers in Immunology, 10. doi:10.3389/fimmu.2019.02630
Mason, D. M., Weber, C. R., Parola, C., Meng, S. M., Greiff, V., Kelton, W. J., & Reddy, S. T. (2018). High-throughput antibody engineering in mammalian cells by CRISPR/Cas9-mediated homology-directed mutagenesis. Nucleic Acids Research, 46(14), 7436-7449. doi:10.1093/nar/gky550
Kelton, W., Waindok, A. C., Pesch, T., Pogson, M., Ford, K., Parola, C., & Reddy, S. T. (2017). Reprogramming MHC specificity by CRISPR-Cas9-Assisted cassette exchange. Scientific Reports, 7. doi:10.1038/srep45775
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