Bernhardt Trout - Extending the shelf life of antibody drugs
New model allows researchers to design more stable drugs
Anne Trafton, News Office
June 29, 2009
A new computer model developed at MIT can help solve a problem that has
plagued drug companies trying to develop promising new treatments made
of antibodies: Such drugs have a relatively short shelf life because they
tend to clump together, rendering them ineffective.
Antibodies are the most rapidly growing class of human drugs, with the
potential to treat cancer, arthritis and other chronic inflammatory and
infectious diseases. About 200 such drugs are now in clinical trials, and a
few are already on the market.
Patients can administer these drugs to themselves, but this requires high
doses - and the drugs must therefore be stored at high concentrations.
However, under these conditions the drugs tend to clump, or aggregate.
Even if they are stored at lower concentrations and administered by a
doctor intravenously, they often have stability issues. Addressing such
issues typically takes place later in the drug development process, and the
cost - both in time and money - is often high.
Currently there is no straightforward way to address these storage issues
early in the development process.
"Drugs are usually developed with the criteria of how effective they'll be,
and how well they'll bind to whatever target they're supposed to bind," says
Bernhardt Trout, professor of chemical engineering and leader of the MIT
team. "The problem is there are all of these issues down the line that were
never taken into account."
Trout and his colleagues, including Bernhard Helk of Novartis, have
developed a computer model that can help designers identify which parts of an antibody are most likely to attract other molecules, allowing them to alter
the antibodies to prevent such clumping. The model, which the researchers
aim to incorporate in the drug discovery process, is described in a paper
appearing in the online edition of the Proceedings of the National Academy
of Sciences the week of June 29.
Most of the aggregation seen in antibodies is due to interactions between
exposed hydrophobic (water-fearing) regions of the proteins.
Trout's new model, known as SAP (spatial aggregation propensity), offers a
dynamic, three-dimensional simulation of antibody molecules. Unlike static
representations such as those provided by X-ray crystallography, the new
model can reveal hydrophobic regions and also indicates how much those
regions are exposed when the molecule is in solution. The other important
aspect of the model is that it selects out regions responsible for
aggregation, as opposed to just single sites.
Once the hydrophobic regions are known, researchers can mutate the
amino acids in those regions to decrease hydrophobicity and make the
molecule more stable. Using the model, the team produced mutated
antibodies with greatly enhanced stability (up to 50 percent more than the
original antibodies), and the mutations had no adverse affect on their
Lead authors of the PNAS paper are Naresh Chennamsetty and Vladimir
Voynov, postdoctoral associates in MIT's Department of Chemical
Engineering. Other authors are chemical engineering postdoctoral
associate Veysel Kayser and Bernhard Helk of Novartis.
The research was funded by Novartis Pharma AG and computer time was
provided in part by the National Center for Supercomputing Applications.
MIT News article.