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

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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.