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8 Nov 2011

Structural analysis indicates how two different antibodies to a cancer-causing protein could work together to block its function

Representation of the binding of pertuzumab (orange) and trastuzumab (black) to the Her2 protein (red/blue)

Representation of the binding of pertuzumab (orange) and trastuzumab (black) to the Her2 protein (red/blue)

© 2011 Fuentes et al

Breast cancer is linked to elevated expression of the cell surface receptor protein human epidermal growth factor 2 (Her2). Two monoclonal antibodies, trastuzumab and pertuzumab, are known to block Her2 function by binding to different portions of the cancer-causing protein, and these antibodies are currently in clinical use to treat breast cancer patients.

In 2010, a team of international researchers including Chandra Verma at the A*STAR Bioinformatics Institute had shown that combining the two Her2-targeting antibodies could offer a more therapeutic strategy than the administration of a single antibody. Now, Verma, together with Gloria Fuentes at the A*STAR Bioinformatics Institute and other co-workers, have used structural modeling techniques to examine the molecular basis of the synergistic effect of trastuzumab and pertuzumab in blocking Her2 function.

The researchers began their investigations by assuming that both antibodies work together in patients by binding to the same molecule of Her2 and potently inhibiting its function. Previous studies had focused on the structure of the Her2 protein alone, along with its points of contact with either trastuzumab or pertuzumab. Verma, Fuentes and their collaborators were able to visualize the complex structure of all three molecules combined using computer models and molecular dynamic simulations. The researchers were able to determine the structural changes that occur as a result of the binding of the two antibodies, and showed that the antibodies bind more tightly to Her2 when they are present together, which would enhance their ability to inhibit Her2 signaling.

Normally, Her2 sends signals into the cell by interacting, or ‘dimerizing’, with other cell surface receptors at the ‘dimerization domain’ portion of the Her2 protein. Pertuzumab binds directly to the dimerization domain, and inhibits Her2 function by preventing Her2 dimerization with its signaling partners. The researchers showed that in the presence of trastuzumab, the Her2 protein appears to become more flexible, which leads to tighter binding of Her2 to pertuzumab. On the other hand, pertuzumab exposes portions of Her2 that had previously been hidden, allowing for more points of contact between Her2 and trastuzumab.

“The ability of the antibodies to work together on the Her2 protein in this way explains, at the molecular level, the higher clinical response previously observed in the patients treated with both antibodies,” says Fuentes. The findings could lead the way to the development of more potent drugs and antibodies to inhibit the activity of Her2 and enhance treatment efficacy for breast cancer patients.

The A*STAR-affiliated researchers contributing to this research are from the Bioinformatics Institute.

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References

Fuentes, G., Scaltriti, M., Baselga, J. & Verma, C. S. Synergy between trastuzumab and pertuzumab for human epidermal growth factor 2 (Her2) from colocalization: an in silico based mechanism. Breast Cancer Research 13, R54 (2011). | article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature