The ‘Antibodies in solution’ research programme – aims to plug a crucial research gap

The Antibodies in Solution research programme at LINXS aims to increase the fundamental understanding of antibodies, and in time create simulation models and experimental tools that can test and predict antibody behaviour in solutions up to high concentrations.

Anna Stradner is a Professor at the Division of Physical Chemistry at Lund University, and leader of the research programme.

Peter Schurtenberger is founding Director of LINXS, and Professor at the Division of Physical Chemistry at Lund University.

– Up to now, we have rather had a cook and look scenario based on past experience when formulating solutions with antibodies. We lack a fundamental understanding of how antibodies behave in solutions, and at higher concentrations, says founding Director of LINXS, Peter Schurtenberger, Professor at the Division of Physical Chemistry at Lund University.

Antibodies are specialised, Y-shaped proteins, that can protect the body against viruses, bacteria, and fungi. The antibody sticks to a protein called an antigen. The antibodies find and attach to the antigen, and can make the immune system destroy the cells containing the antigen. Monoclonal antibodies are becoming of increasing interest to the pharmaceutical and medical industries for their potential to be used as disease treatments, including some types of cancer. Industrially produced antibodies are usually made from mouse proteins, a combination of human and mouse protein, and mouse protein attached to a human protein.

Expensive to produce and many unanswered research questions

Yet, many questions on how antibodies behave in solution, particularly at higher concentrations, remain to be solved. Another aspect is that antibodies are currently very expensive to produce. This has to do with the need of extensive preproduction efforts to ensure that the antibody can be produced in great quantities, and that it is stable, and not contaminated. The production also requires high-quality specialized technical equipment. This has severely hampered systematic fundamental studies by individual research groups.

It exists a clear need for a major collective effort in order to secure sufficient amounts of well-defined antibodies and perform a concerted research investigation that covers all relevant length and time scales needed to understand the physical properties of individual antibodies as well as those of concentrated solutions. At LINXS, a research programme on antibodies was thus created two years ago, in 2018, to tackle these problems. The research programme gathers 14 international research groups, with four groups from Lund University, as well as pharmaceutical companies and the American National Institute of Standards and Technology (NIST). In mid-December, they had a kick-off for all the members of the programme.

– We have been working together since 2018 but our main challenge has been to get hold of an appropriate set of antibodies to use for our experiments. Access to sufficient amounts of high quality antibody material is the basic prerequisite for our programme. Now, finally, we are hoping to receive antibodies from NIST in 2021, says Anna Stradner, Professor at the Division of Physical Chemistry at Lund University, who is leading the programme.

Anna Stradner and Peter Schurtenberger explain that an overarching aim of the programme is to investigate the step between antibody production and drug development. Currently there is no coherent study of how antibodies behave on a fundamental level in solution at higher concentrations. For example, what happens to the antibodies when additives and chemicals are added, or when the pH-value or the storage temperature change?

– This type of research is very important in terms of understanding how to use antibodies, and in what concentrations. If you inject a medicine, you cannot administer too large volumes, meaning you have to go for relatively high antibody concentrations in order to provide a physiologically effective dose in one shot. Similarly, you do not want the solution to be too viscous since it can be difficult and painful to inject, says Peter Schurtenberger.

Study behaviour with different techniques

Once the programme receives the antibodies, the research groups will start to apply different complementary methods to investigate the behaviour of the antibodies under carefully predefined conditions and characterize them.

– Antibodies are very complex proteins. Using different techniques will therefore be key to understand their behavior on a fundamental level. We will use x-ray and neutron scattering techniques together with relevant complementary methods and advanced data analysis tools to get as broad a picture as possible, says Anna Stradner.

Ideal result for the research programme – from individual antibodies to model systems

When asked what they would like to see as the outcome of the research programme, Anna Stradner and Peter Schurtenberger emphasise two things: simulation models and tools.

– We want to be able to test individual antibody behaviour at an early stage of development, where only small amounts of the precious antibody are available. Can we predict how the antibody will behave in solution at higher concentrations based on what we have learned from the model systems that we have developed? says Anna Stradner.

More fundamental knowledge on antibody solution behaviour can in time revolutionize drug development and use of antibodies believe the researchers.

– What we are doing here is a fairly unique effort in terms of filling a research gap of broad societal interest. We are gathering theorists and experimentalists from across the world, to look into an area that is yet under researched, says Peter Schurtenberger.

LINXS has played a crucial part in making the work possible.

– The power of LINXS is to act as a good broker. It gave us a platform to gather researchers from different fields to work together on this project. This is a classic example of what an organisation such as LINXS can do for science, in terms of supporting this type of bottom-up initiative to grow, concludes Peter Schurtenberger.