23 Dec 2015

Merck scientists gain insight into cancer treatment

A team of scientists at Merck in Kenilworth, NJ have used the Canadian Light Source facilities to collect data used to determine the structure of a brand new cancer-treating antibody, providing an unprecedented level of detail.

The antibody, pembrolizumab, works by increasing the ability of the body’s immune system to help detect and fight tumor cells.

Certain cancer cells are able to express PD-L1 molecules which interact with PD-1 molecules on immune cells, inhibiting the immune response. Pembrolizumab blocks this interaction, thereby restoring the ability of the immune system to mount an immune response against the cancer cell.

The results generated by Dr. Giovanna Scapin and her structural chemistry colleagues, which were recently published in Nature Structural and MolecularBiology, provide a three-dimensional structure of pembrolizumab at an incredible 2.3 angstrom resolution, a level of detail 100 billion times smaller than a centimeter.

“The atomic interactions become much clearer at that level, it’s just a whole other world from even a three angstroms resolution,” says Scapin. “The structure to me represents a total novelty, it was something that we had never seen before.”

Pembrolizumab belongs to the IgG4 class of antibodies, which have been shown to have different properties from other antibody classes for which three-dimensional structures have been made available. For IgG4 antibodies, previous studies had only looked at fragments. The new data provide a more complete picture of the structure of an IgG4 antibody and offer potential reasons for their unique behavior.

Scapin also notes that understanding the three-dimensional structural details of a therapeutic antibody can help in understanding its physical properties and how it interacts with its receptor, which may help in refining the manufacturing process or lead to other modifications designed to improve its therapeutic properties.

The three dimensional structure of pembrolizumab reveals novel characteristics that appear to be unique to the IgG4 class of antibodies and may explain their unusual behaviors.
Cite: Scapin, Giovanna, Xiaoyu Yang, Winifred W. Prosise, Mark McCoy, Paul Reichert, Jennifer M. Johnston, Ramesh S. Kashi, and Corey Strickland. "Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab." Nature structural & molecular biology (2015).

 

 

 

 

 

 

 

 

 

 

 

About the Canadian Light Source Inc.:

The CLS is the brightest light in Canada—millions of times brighter than even the sun—used by scientists to get incredibly detailed information about the structural and chemical properties of materials at the molecular level, with work ranging from mine tailing remediation to cancer research and cutting-edge materials development.

The CLS has hosted over 2,500 researchers from academic institutions, government, and industry from 10 provinces and 2 territories; delivered over 40,000 experimental shifts; received over 10,000 user visits; and provided a scientific service critical in over 1,500 scientific publications, since beginning operations in 2005. The CLS has over 200 full-time employees.

CLS operations are funded by Canada Foundation for Innovation, Natural Sciences and Engineering Research Council, Western Economic Diversification Canada, National Research Council of Canada, Canadian Institutes of Health Research, the Government of Saskatchewan and the University of Saskatchewan.

For more information visit the CLS website or contact:

Victoria Martinez
Communications Coordinator 
1 (306) 657-3771
victoria.martinez@lightsource.ca

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