New model could improve some drugs' effectiveness

Sep 23, 2007
New model could improve some drugs' effectiveness
In this image, a fragment of the antibody Erbitux (cetuximab) binds to its target, a fragment of epidermal growth factor receptor (EGFR). The blue ribbon at the top is the backbone of the EGFR fragment, and the red and gray ribbons at the bottom are the backbone of the antibody fragment. The licorice sticks and the balls in the central portion represent protein side chains making close interactions between the antigen (EGFR) and the antibody, with the balls representing one of the mutations designed computationally. Image / Shaun Lippow

MIT researchers have developed a computer modeling approach that could improve a class of drugs based on antibodies, molecules key to the immune system. The model can predict structural changes in an antibody that will improve its effectiveness.

The team has already used the model to create a new version of cetuximab, a drug commonly used to treat colorectal cancer, that binds to its target with 10 times greater affinity than the original molecule.

The work, which will appear Sept. 23 in an advance publication of Nature Biotechnology, results from a collaboration using both laboratory experiments and computer simulations, between MIT Professors Dane Wittrup and Bruce Tidor.

“New and better methods for improving antibody development represent critical technologies for medicine and biotechnology,” says Wittrup, who holds appointments in MIT's Department of Biological Engineering and Department of Chemical Engineering. Tidor holds appointments in Biological Engineering and the Department of Electrical Engineering and Computer Science.

Antibodies, which are part of nature's own defense system against pathogens, are often used for diagnostics and therapeutics. Starting with a specific antibody, the MIT model looks at many possible amino-acid substitutions that could occur in the antibody. It then calculates which substitutions would result in a structure that would form a stronger interaction with the target.

“Combining information about protein (antibody) structure with calculations that address the underlying atomic interactions allows us to make rational choices about which changes should be made to a protein to improve its function,” said Shaun Lippow, lead author of the Nature Biotechnology paper.

“Protein modeling can reduce the cost of developing antibody-based drugs,” Lippow added, “as well as enable the design of additional protein-based products such as enzymes for the conversion of biomass to fuel.” Lippow conducted the research as part of his thesis work in chemical engineering at MIT, and is now a member of the protein engineering group at Codon Devices in Cambridge, Mass.

“Making drugs out of huge, complicated molecules like antibodies is incredibly hard,” said Janna Wehrle, who oversees computational biology grants at the National Institute of General Medical Sciences, which partially supported the research. “Dr. Tidor's new computational method can predict which changes in an antibody will make it work better, allowing chemists to focus their efforts on the most promising candidates. This is a perfect example of how modern computing can be harnessed to speed up the development of new drugs.”

Traditionally, researchers have developed antibody-based drugs using an evolutionary approach. They remove antibodies from mice and further evolve them in the laboratory, screening for improved efficacy. This can lead to improved binding affinities but the process is time-consuming, and it restricts the control that researchers have over the design of antibodies.

In contrast, the MIT computational approach can quickly calculate a huge number of possible antibody variants and conformations, and predict the molecules' binding affinity for their targets based on the interactions that occur between atoms.

Using the new approach, researchers can predict the effectiveness of mutations that might never arise by natural evolution.

“The work demonstrates that by building on the physics underlying biological molecules, you can engineer improvements in a very precise way,” said Tidor.

Expanding on that theme, Wittrup and Tidor also co-teach a class and are writing a textbook focusing on connecting fundamental molecular and cellular events to biological function through the use of mathematical models and computer simulations.

The team also used the model with an anti-lysozyme antibody called D44.1, and they were able to achieve a 140-fold improvement in its binding affinity. The authors expect the model will be useful with other antibodies as well.

Source: Massachusetts Institute of Technology

Explore further: Chickens to chili peppers: Scientists search for the first genetic engineers

add to favorites email to friend print save as pdf

Related Stories

A microchip for metastasis

Feb 06, 2014

Nearly 70 percent of patients with advanced breast cancer experience skeletal metastasis, in which cancer cells migrate from a primary tumor into bone—a painful development that can cause fractures and ...

Biomolecules for the production line

Oct 01, 2013

To produce proteins on an industrial scale without using living cells is the ambitious goal of cell-free bioproduction. This method could help us to produce biological ingredients more quickly and with fewer ...

Nanosensors could aid drug manufacturing

Aug 16, 2013

MIT chemical engineers have discovered that arrays of billions of nanoscale sensors have unique properties that could help pharmaceutical companies produce drugs—especially those based on antibodies—more ...

Recommended for you

Scientists tether lionfish to Cayman reefs

1 hour ago

Research done by U.S. scientists in the Cayman Islands suggests that native predators can be trained to gobble up invasive lionfish that colonize regional reefs and voraciously prey on juvenile marine creatures.

Deadly human pathogen Cryptococcus fully sequenced

12 hours ago

Within each strand of DNA lies the blueprint for building an organism, along with the keys to its evolution and survival. These genetic instructions can give valuable insight into why pathogens like Cryptococcus ne ...

User comments : 0

More news stories

Scientists tether lionfish to Cayman reefs

Research done by U.S. scientists in the Cayman Islands suggests that native predators can be trained to gobble up invasive lionfish that colonize regional reefs and voraciously prey on juvenile marine creatures.

Deadly human pathogen Cryptococcus fully sequenced

Within each strand of DNA lies the blueprint for building an organism, along with the keys to its evolution and survival. These genetic instructions can give valuable insight into why pathogens like Cryptococcus ne ...

Biologists help solve fungi mysteries

(Phys.org) —A new genetic analysis revealing the previously unknown biodiversity and distribution of thousands of fungi in North America might also reveal a previously underappreciated contributor to climate ...

Leeches help save woman's ear after pit bull mauling

(HealthDay)—A pit bull attack in July 2013 left a 19-year-old woman with her left ear ripped from her head, leaving an open wound. After preserving the ear, the surgical team started with a reconnection ...

Venture investments jump to $9.5B in 1Q

Funding for U.S. startup companies soared 57 percent in the first quarter to a level not seen since 2001, as venture capitalists piled more money into an increasing number of deals, according to a report due out Friday.