When antibodies attack: deciphering molecular mysteries of the immune system

In the past decades, huge progress has been made in the development of novel therapeutics to target hard-to-treat illnesses. Monoclonal antibodies (mAbs) - laboratory-designed proteins inspired by our immune system - have been an essential milestone in this context. Today, mAbs have become crucial therapeutic agents in the fight against a wide range of conditions such as certain cancers, autoimmune diseases or chronic migraines.

mAbs are Y-shaped molecules, with the two arms of the Y being responsible for specific binding to their target such as a tumour cell or virus and the leg responsible for communication with the immune system, e.g. to talk to a killer cell. These regions are connected via a flexible molecular linker which grants them flexibility.

Therapeutic mAbs are usually administered in the form of highly concentrated injections. These elevated concentrations imply high solution viscosities, which can interfere with molecular motions of the mAbs and with their ability to interact with their target molecules. Understanding these interactions with molecular precision is an essential step to optimise the development of future mAb formulations. This was the goal of a study conducted by a team of researchers from Germany in collaboration with ILL scientists.

“We wanted to learn as much as possible about how mAbs move in highly concentrated solutions, and about the internal movements that help them find their target binding site,” explained Ralf Biehl and Andreas Stadler, two of the authors of the study, recently published in the scientific journal Communications Biology.

The team’s research was enabled by ILL’s cutting-edge neutron expertise, notably its advanced instrumentation for quasielastic neutron scattering. “Techniques such as neutron spin-echo allow us to detect extremely small energy exchanges between neutrons and a sample - in this case, mAb solutions - by monitoring changes in the neutrons’ spin as they interact with the sample”, explains Orsolya Czakkel, instrument responsible of IN15, one of the neutron spin-echo spectrometers at the ILL. This makes the method especially well-suited for investigating subtle molecular motions with exceptionally high resolution. 

The researchers identified two main types of internal antibody movement: the ‘search’ motion and the ‘attack’ motion. The former describes how the antibody’s ‘arms’ and ‘legs’ prepare to find their target, while the latter represents the actual approach to the binding site. Interestingly, the 'attack' motions remain even at very high mAb concentrations, while the ‘search’ motions progressively decrease. This is good news, as it means that their biological functionality remains intact even in a crowded environment close to a tumour cell or a virus wall.

The team's results further revealed that the antibody's overall movement is strongly dependent on the flexible linker region, which acts as a molecular ‘spring’ that drives attack motions.

“Our findings imply that optimising the design of the linker regions of therapeutic antibodies would allow for better binding to their respective targets,” the researchers explained. “This is crucial information in light of the constant search for highly targeted, personalised medical treatments.”