We have developed a very successful range of software and databases for analysis of antibody sequence and structure. In particular, abYsis [1] (
http://www.abysis.org) is widely used online and is successfully sold to companies for in-house use. Antibodies have shown a huge degree of success as novel therapeutics with ~100 currently licensed in Europe and the US and >170 in development for Covid-19 alone. The related T-Cell Receptors (TCRs) are now being exploited as a novel form of therapy [2,3]. This project will repurpose methods we have developed for antibodies for use with TCRs as well as developing new approaches and performing new analyses. Software (based on our abnum program [4]) will be developed to apply standard numbering to TCRs, such that sequence and structure features can be analyzed. Tools will be developed to store and analyze public sequence and structure data with a view to producing software that can be used in the development of TCR-based drugs. Crystal structures will be analyzed to look at domain packing which can be exploited to improve TCR modelling as we have done for antibodies [5] (
http://abymod.abysis.org/). Huge nextgen TCR sequence datasets will then be analyzed taking a ‘big data’ approach storing sequence data, analyzing residue distributions and adding annotations, triaging sequences at each step to reduce unnecessary analysis. Triage will include screening out very unusual sequences and those with likely immunogenicity or developability issues. A basic web interface will be developed to allow the data to be explored and new sequences to be analyzed.
With our industrial partners, this will contribute to the development of new biologic drugs used as targeted therapies for use in specific cohorts of patients in fields including infection, autoimmune/inflammatory disease and cancer.
The project will involve regular visits to Immunocore including a placement of at least 3 months to generate TCR sequence datasets and to better understand the developability needs of their soluble TCR platform. Immunocore will provide training and mentorship in the areas of TCR discovery, TCR structure , developability of TCRs as soluble therapeutic agents, molecular cloning, protein expression, library preparation and mutagenesis, screening for binding, BIAcore, and structural studies as and when appropriate for the project. This translational project is expected to result in at least 3 papers being published and it will contribute to software licensing encompassing ‘big data’ and data science. The project will provide training in the biology of TCRs, the nature of NGS sequence data, big-data databases and software development. It will provide for personal development and acquisition of translational skills beyond a purely academic setting. The training will not only be in individual techniques, but also in the development of a pipeline from basic science to translation.
