Structural changes of interfacially adsorbed antibody molecules

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Natural proteins such as antibodies (mAbs) have vastly different sequences, sizes, shapes and globular stability. It is difficult to establish common features linking their sequences to domain stability and that of the whole mAb. Thus, current knowledge of protein adsorption and desorption is very limited at predicting how bioengineered mAbs behave.

MedImmune has designed and bioengineered a group of mAbs from the native human IgG1, with careful sequence modifications in Fab, Fc, other receptor binding domains and connection domains. Because of their well-controlled sequence changes and stability design, these mAbs are not only important for biotherapeutic development but also crucial to the development of new scientific understanding.

Specifically, we will have two lines of work tasks to pursue. Firstly, we will examine how sequence modifications affect the adsorbed structures of Fab and Fc with regard to the extent of deformation of globular domains and the impact on the whole mAb. Secondly, we will examine how the different nature of substrate surfaces affects adsorption and deformation, again focusing on the extent of structural deformation and possible unfolding. It is especially useful to explore how the extent of deformation and unfolding which is likely to be affected by sequence modification, solution conditions and adsorption time, is affected by the nature of the different substrates.

An important technical advance that will emerge from this project is the development of the capability of molecular dynamics (MD) simulation to analyse neutron reflectivity data, providing structural conformations of adsorbed mAbs with unprecedented resolution. Concomitantly, MD will also be able to develop its own predictive power in modelling mAb adsorption and desorption. The combined use of the two techniques will lead to development of a software package with the capability to predict adsorption and desorption of mAbs and other proteins.

Societal impact and responsibility: In spite of the huge advances, chemotherapy combined with radiotherapy currently remains the mainstream cancer treatment for patients. Unfortunately, toxicity and other related side-effects constrain survival rates. However, new treatments combining biomarker-based gene therapies and immune therapies are rapidly increasing, with these new drugs dominating the market sales. These new drugs are clearly performing better in avoiding the drawbacks from chemotherapy, but are still far from perfect, and further research is needed to overcome these technical hurdles. With MedImmune's support, we will develop online materials to highlight the pros and cons of current cancer treatments, seeking public support towards developing new and better treatments through collaborative research. Cancer prevention and early diagnosis are better options than treatment. As the research project develops, we will write popular cancer educational articles targeting the general public, explaining how to prevent developing cancer by changing lifestyles, using existing literature on prostate cancer as an example. With our expertise in reliable data treatment, we will be able to critically review the relevant publications on this topic, presenting a balanced view of the statistical significance (or otherwise) of the literature.

Cancer screening - Prevention by lifestyle changes is clearly the best option, but screening is preferable to treatment. There are several UK websites devoted to prostate cancer, and there is now a national awareness of the need for men below 55 years old to undertake prostate screening. Cancers usually have approximately 20-year incubation periods, and early screening could save lives and resources for the NHS. We will look into the difficulties in implementing early screening programmes within the NHS, and explore possible alternatives by reviewing practices used in the USA, again aiming at the general public in these articles.

International development - Cancer rates are strongly correlated with life expectancy and wealth: highly developed countries such as Denmark, France and Italy have 40% more cancer cases per head of population than poor countries. In addition, the top five cancers in rich nations are in the order of breast, lung, prostate, colon, and stomach, whilst in poor countries these are in the different order of lung, stomach, breast, liver and colon. Apart from environmental factors, aspects such as smoking, alcohol, food, exercise, exposure to radiation, chronic infection, immune compromise, etc have been identified as causal factors in cancer. We will introduce examples of classical research publications in this area to the general public, e.g., the effect of the smoking ban in the USA on the significant reduction of lung cancer incidence.

Business development and wealth creation - MedImmune is one of the major antibody biotherapeutic companies in the world. As the key joint partner in this project they will be the first to consider the implications of the new results on their formulation and product development. The new knowledge will help support redesign and reformulation of existing products, or new product development. UoM and IC will strengthen their links with MedImmune and could develop new collaborations. Any new IP in surface modifications (UoM) and software capability (IC) will be protected by their respective university IP bodies.

Skills training opportunities - The two RAs will receive interdisciplinary training between physics and biology. They will also receive training from the collaborating industrial partner, and have opportunities to organise and participate in workshops. They will also disseminate their results to research students and academics in other fields, through joint project seminars, group seminars, department/school open days and visits to local schools.