Translation of antibody-dependent cell cytotoxicity (ADCC) from in vitro to in vivo

Antibody-dependent cellular cytotoxicity (ADCC) is a primary effector function of monoclonal antibodies (mAbs), which enables the targetted killing of cells such as tumour cells by the immune system. The three best selling cancer drugs utilize ADCC but it has also been utilized in other areas to reduce B-cell levels in patients with auto-immune diseases and as therapy for Epstein-Barr virus patients who have just received a bone-marrow transplant. There have been efforts to model this process in the literature where Michaelis-Menten like models and stochastic models have been used to simulate ADCC potency within in vitro assays. The most recent mechanistic model by Hoffman et al. linked antibody levels to ADCC potency for different immune:target cell ratios. However, these models fail to capture the multi-scale complexity of this process as a whole and to the best of our knowledge, there does not exist either a multi scale model or in vivo model for ADCC in the literature despite how common this effector function is in mAb therapies. The development of mechanistic models that accurately describe the full complexity of ADCC and other antibody effector functions will inform future antibody design and begin to enable extrapolation of in vitro to in vivo data. The aims for this project include the development of a micro-scale (receptor level) model for ADCC and then to translate this to a macro-scale (cell level) model. These models and their analysis will then be used to inform an in vivo model of ADCC. Other similar antibody effector functions and immune cells will also be considered and models will be validated with data where available. An ultimate objective for this project is to use the models developed and their insights to inform aspects of clinical trials such as patient susceptibility to ADCC-based therapeutics, minimum antibody-dose concentration needed for a therapeutic effect and the incorporation of patient data into models to predict ADCC potency within the patient, linking this to clinical outcome. Novel aspects of the research methodology include detailed modelling of receptor-level processes such as binding avidity in the micro-scale model, techniques to formulate and compute a multi-scale of ADCC by combining the micro and macro scale models, translating ADCC from in vitro to in vivo and the formulation of agent-based model (ABM) PDE models for ADCC processes with mathematical consideration of if or when the ABM can be reduced to the PDE. This project will be in collaboration with GlaxoSmithKline and will cover areas in mathematical oncology, mathematical immunology and computational biology. As such, this project falls within the EPSRC mathematical biology, mathematical sciences and physical sciences research areas.

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.