Development of machine learning tools to improve the developability of therapeutic antibodies.

Antibodies are a popular therapeutic format due to their ability to specifically target any molecule. Therapeutic antibodies have been successfully developed to target a variety of diseases, including cancer and infectious diseases. However, therapeutic antibody development is a complex and expensive task. Even if a candidate is a strong and specific binder, it may suffer from developability issues - such as high immunogenicity, instability, self-association, high viscosity, polyspecificity, or poor expression - which may make it untenable as a therapeutic. It is therefore important to recognise and flag any issues as early as possible in the drug discovery pipeline. Many such issues arise due to structure-based biophysical properties of the antibody. Current tools exist which are able to calculate these properties and flag such developability issues, such as the Therapeutic Antibody Profiler (TAP). However, there is currently no tool capable of multi-objective structural optimisation of these flagged candidates, removing developability issues while retaining antigen binding properties. Development of such a tool would prove invaluable in preventing high affinity antibodies that are flagged as undevelopable from being discarded from the drug discovery pipeline. This would save money, help diversify lead therapeutics, and potentially unlocking new targets. This project aims to create such a tool, capable of suggesting mutations to overcome developability issues for an antibody, while also retaining binding affinity for its target epitope. For a multi-optimisation problem like this, a machine learning (ML) model would be well suited. The ML model developed will take advantage of state-of-the-art deep learning advances, such as equivariant graph neural networks and transformers. Advances in the accuracy of computational structural modelling of antibodies (e.g. ABlooper) allows for a structure-aware approach to be taken. Rules based limitations on the mutational space can also be integrated into the model to prevent a reduction in antigen binding affinity. The project falls within the EPSRC chemical biology and biological chemistry theme. The project is based at the Oxford Protein Informatics Group, Department of Statistics in collaboration with AstraZeneca UK, with academic supervision by Professor Charlotte Deane, and industrial supervision by Dr Rebecca Croassdale-Wood. AstraZeneca are providing antibody synthesis and assaying capabilities, allowing experimental validation of model predictions.

The main impact of the SABS CDT will be the difference made by the scientists trained within it, both during their DPhils and throughout their future careers.

The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.

Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners

"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."

New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.

For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,

"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."

However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.

The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students

"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."

To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.

The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.