The newly published research in Cell reveals why mAbs often form clusters that lead to high viscosity in drug solutions. The research could be a boon for drug companies looking to create a variety of mAb treatments for cancer and autoimmune diseases but where high viscosity hinders their ability to be delivered through thin needles.
mAbs are Y-shaped protein molecules where the tip region of two of their "arms" can be engineered to attack tumor cells without harming surrounding tissue, which makes mAbs less dangerous than standard chemotherapy, researchers said. However, a roadblock in their potential as subcutaneous injections —the preferred delivery technique— is their high viscosity. In solution, some mAbs become so viscous at required high concentrations that they are nearly impossible to inject.
High concentration formulations can also reach high viscosities that make them difficult to manufacture, limit delivery options, or require costly special delivery methods.
MAbs with low enough viscosity can be injected, but pharmaceutical firms still don't know why some other mAbs stick together so tightly that they cannot be injected.
The NIST Center for Neutron Research (NCNR), however, is looking to change that as it can take a picture of protein motions at a timescale of less than half a microsecond, which is fast enough to see how they change their orientations and move together in solution.
"When you put these mAbs in water, they twist around and stick to one another. We wanted to explore the fundamentals of viscosity by understanding the molecular structure as it develops, so we can model it better," Yun Liu of the NCNR said, according to NIST.
Neutron Spin Echo Instruments
Using the neutron spin echo instruments at NCNR and Institut Laue-Langevin, scientists from several institutions found out that in the high concentrations, mAbs tend to partner, forming strongly bounded clusters made primarily of two protein molecules at a time, with an arm from one molecule linked by electrical attraction to a different arm on another.
Liu added that understanding the ability of mAbs to stick together allows him and his fellow scientists “to model these protein clusters, so we can do simulations about their behavior based on their sequence. It offers a guide for drug companies to formulate similar types of proteins in the future."