Neutron analysis reveals cancer drug clustering
30 May 2014 by hjqbcptqcm.d hjqbcptqcm.d
Cancer pharmaceuticals currently have to be administered intravenously because of a tendency for solutions containing high concentrations of some antibodies to be highly viscous.
Not only does this prevent large scale production and purification, but delivery of the drug via syringe too. Now researchers from the Institut Laue-Langevin have discovered what causes this high viscosity.
Using a neutron spin echo technique, researchers observed how different particles move during their diffusion in water. In order to see how increased antibody concentration affected the overall property of a solution, they studied two types of antibody – one known to increase solution viscosity and one which didn’t have any effect.
The technique confirmed that the source of the viscosity increase was a clustering of antibody proteins, likely caused by binding between the antibody’s long arm-like structures.
Researchers also identified a potential difference in the two antibodies studies which explains why one clustered and one didn’t and could be used to reduce viscosity of cancer treating monoclonal antibody solutions. Cluster formation is determined by different distributions of electric charge within the critical complementary determining region (CDR) of the antibody – the part which binds to the specific antigen.
“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,” said Dr Peter Falus, instrument scientist at ILL. “A lot of well-known phenomenon, such as the cataracts in our eyes, or Alzheimer’s disease, are the result 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 results could be an important first step in increasing the concentrations of pharmaceuticals used to treat cancer, arthritis and multiple sclerosis. The next step is to use these insights to model how these antibodies can be tweaked in order to produce and deliver effective drugs. Computer simulations have already tested the effect of changing properties in the key CDR zone and confirmed theories around the important role played by electrical charge distribution.
The work, which also included researchers from the NIST Centre for Neutron Research and the University of Delaware, has been published in Biophysical Journal.
