Sugar-blocking Technology “Supercharges” Antibodies to Fight Cancer

• By uncovering how sugars influence biological processes, glycomics researchers are creating new solutions to pressing health challenges.

Research teams led by GlycoNet investigators Drs. David Vocadlo and Rob Britton have teamed up to develop a technology that could lead to new cancer treatments. They’ve created a molecule that modifies the sugars on therapeutic antibodies in a way that equips them to fight cancer cells more effectively.

“The improved antibodies can bind up to 50-fold more potently, making them far more effective, and this can also allow you to target cancers that you wouldn’t normally be able to attack using a standard anti-cancer antibody,” explains Vocadlo, professor at Simon Fraser University (SFU) and head of one of the laboratories involved in the project. 

The molecule, named β-carbafucose, acts as a mimic to “block” a sugar called fucose from being attached to the antibodies. Fucose is one type of monosaccharide or sugar that is normally present in sugar chains (called glycans) on therapeutic antibodies.

“Imagine a tree is the whole glycan and each branch is one monosaccharide. We’re just cutting off one branch of the glycan,” explains Vocadlo. 

The resulting antibodies with fucose removed are then known as afucosylated antibodies.

Other approaches to making afucosylated antibodies often have limitations or undesirable outcomes. For example, one method involves genetically engineering cell lines (lab-grown cells that divide indefinitely) to “knock out” the enzymes that play a role in attaching fucose. The problem with this approach is it requires significant time and effort.

“You have to recertify cell lines and you have to deal with the fact that these engineered cell lines often don’t grow as well or express as much antibody,” says Vocadlo. “It’s a long process of trying to identify a line that grows properly and that produces lots of antibody, so that you can take that onward for potential commercial use.” 

Some companies have also tried creating small molecules that mimic fucose, but these molecules often become integrated as part of the final therapeutic antibodies, and this has led to worries about undesirable effects.

Vocadlo’s team realized a way around this problem and joined forces with Britton’s team to create a molecule that cannot be transferred to the antibodies. Britton’s team developed an efficient chemical synthesis of β-carbafucose, enabling the molecule to be made in an easy and inexpensive way.

“It will allow people to rapidly access, test and screen for these types of afucosylated antibodies that potentially are much better at combatting cancers,” says Britton, professor at SFU and head of the other laboratory involved in the project.

“We went on to show that you can reliably generate therapeutic antibodies that have no fucose, including at large scale. We hope it’s going to be useful for the wider community because it can enable very rapid production of these types of afucosylated antibodies.”

In addition to applications in medicine, this new molecule will serve as a useful tool for researchers to study and better understand the roles of fucose in different biological functions.

From Collaboration to Commercialization

The research involved significant collaboration, with teams from Simon Fraser University, University of British Columbia, Academia Sinica (Taiwan) and Catalent Pharma Solutions.

The team’s technology is currently being developed and commercialized by Carbaform Biosciences, a spinoff company founded by Vocadlo and Britton, who brought on board industry expert Dr. David Rabuka.

Dr. V Narasimharao Thota led the chemical synthesis and Dr. Pierre-André Gilormini was heavily involved in the biology associated with the project. Gilormini is also lead author on the team’s recent paper published in the Proceedings of the National Academy of Sciences (PNAS).

The study acknowledges support from GlycoNet, Natural Sciences and Engineering Council of Canada, Michael Smith Foundation for Health Research, Canadian Institutes of Health Research, Pacific Parkinson’s Research Institute, CFI John Evans Leaders Fund and Academia Sinica.

Original source here.