Lowering the viscosity of cancer pharmaceuticals
Scientists have confirmed why cancer pharmaceutical solutions thicken, a phenomenon that limits the concentration of treatments administered to patients around the world. Using a neutron spin echo technique at the Institut Laue-Langevin (ILL), the team of researchers from ILL, the NIST Center for Neutron Research (NCNR), and the University of Delaware have provided insights that could be used to offer suffers of cancer, arthritis and multiple sclerosis the opportunity to administer their own drug treatment from home.
Monoclonal antibodies are proving themselves a vital tool in modern pharmacology, providing the basis for a growing number of successful drugs. An agent for targeted therapy with few side effects, they are an alternative to more invasive treatments such as chemotherapy as they work by attaching themselves to specific proteins on cancerous cells.
Unfortunately, their success comes at a price - treatments are often very expensive and impractical, due in part to the need for them to be given intravenously through a drip. Attempts have been made to redesign the treatments to allow for easier and cheaper subcutaneous delivery (a shallow injections into the cutis just below the skin) such as the home treatments offered to sufferers of type 1 diabetes. However, progress has been hampered by the tendency of solutions containing a high concentration of some antibodies to be highly viscous which prevents large scale production, purification, and delivery of these drugs.
"From some proteins you literally can't get them out of the needle at these higher concentrations and the only option is repeat visits to the hospital with intravenous drips," explains Prof. Yun Liu at University of Delaware."
As a result, global efforts to raise the concentration of monoclonal antibody pharmaceuticals are focused on understanding the exact cause of this thickening.
In this latest study, Prof. Liu and his collaborators used a neutron spin echo technique at the Institut-Laue-Langevin in Grenoble and NCNR in USA to study how increased antibody concentration affects the solution's overall properties. Two types of antibody were placed in solution - one known to increase solution viscosity and one which didn't have any effect - so any differences in behaviour could be observed.
Neutron spin echo allows scientists to see how and how fast different particles move, particularly during their diffusion in water. Using this technique the team confirmed that the source of the viscosity increase was a clustering of antibody proteins, most likely caused by binding between the antibody's long arm-like structures. They also identified a potential difference in the two antibodies studied that explains why one clustered and one didn't, which could be used in future to reduce the viscosity of cancer treating monoclonal antibody solutions.
Prof Liu and his collaborators suggest that different distributions of electric charge within the critical complementary determining region (CDR) of the antibody, the part which binds to the specific antigen, determines the formation of these clusters
Dr Peter Falus, instrument scientist at ILL said: "Whilst the potential impact of these studies on drug design is very exciting, the subject of protein clustering is an extremely interesting area in its own right. A lot of well known phenomenon, such as the cataracts in our eyes, or Alzheimer's disease are the results of proteins clustering in our bodies. As a physicist, I am also interested in clustering in general and neutron techniques here at the ILL provide a unique tool to investigate these complex interactions in natural organic systems."
The next steps are to use these insights to start modeling how these antibodies can be tweaked in order to produce and deliver effective drugs. Prof Liu and his colleagues have already begun to run computer simulations to test the effect of changing the properties in the key CDR zone which have backed up their theories around the important role played electrical charge distribution.