Antibody drug Discovery - in-silico binder prediction

Antibody drug Discovery - In-silico binder prediction, DPhil project summary Advances in machine learning have allowed the development of software that accurately predicts the structure of proteins. The next big step in the field is to essentially to reverse this process. Protein design aims to predict protein sequences that will adopt a certain fold and perform a desired function. The ability to design artificial proteins would lead to major advances in healthcare and biotechnology. My DPhil project will be focussed on the in-silico design of antibodies with specified binding properties. An important step in designing antibody binders is the accurate quantification of binding affinities. However, it remains a major challenge to do this with computational methods and experimental techniques are time-consuming and hard to perform at the necessary scale. Limited understanding of protein flexibility is believed to be a main factor why we struggle to predict binding affinities. Proteins are generally highly flexible molecules and a single structure is rarely able to explain their functions. Thus, research has started to shift its focus on studying the dynamics of proteins and the structural ensembles they adopt. In this project, I aim to build on recent advances in protein structure prediction tools. Current tools are able to accurately predict a single structure for a given amino acid sequence. As more and more data about the dynamics and flexibility of proteins is becoming available, I aim to develop a ML-based tool that is able to determine the flexibility of antibody CDR loops and predict the structural ensemble they adopt. Using this tool, I aim to investigate retrospectively what sequence and structural features make some loops flexible in confirmations and some static. This will help to gain a better understanding of protein flexibility rather than simply using ML as an inexplicable black box. Only limited computational tools are available to predict protein flexibility and confirmational ensembles. Most current tools are based on Molecular Dynamics simulations, which often struggle to produce physiologically correct results. As more experimental data on protein dynamics becomes available, it is expected that ML-based technologies will be able to use this data to make accurate predictions. If successful this would be one of the first ML tools able to predict protein flexibility and contribute to the emerging field of protein design. This project falls within the EPSRC synthetic biology and artificial intelligence technologies research areas as it attempts to apply state-of-the-art machine learning methods for the design of novel biologically active molecules. The project is in collaboration with Roche as an industrial partner.

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.