How sugar mimics could help enhance the effectiveness of antitumor antibodies
GlycoNet researchers at Simon Fraser University are developing new molecules with the ultimate goal to improve the effectiveness of antitumor antibodies
By Ali Chou
Carbohydrate mimics, or compounds that look and sometimes behave like sugars, have attracted much attention from pharmaceutical companies due to potential applications as anticancer and antibacterial drugs. Yet, creating carbohydrate mimics is not straightforward. Often, their synthesis involves many complicated synthetic manipulations or ‘steps’, which require excessive amount of time and resources.
As a medicinal chemist, GlycoNet Investigator Dr. Robert Britton has another plan. He has spent more than five years developing and demonstrating a novel synthetic route to make carbohydrate mimics that could help industrial manufacturers improve the production of antitumor antibodies.
“The effectiveness of antitumor antibodies in killing cancer cells depends largely on the structure of the antibodies themselves—particularly, the types of carbohydrates attached to them,” says Britton. “The activities of these antibodies increase significantly if they do not incorporate the carbohydrate ‘fucose’.”
The discovery of non-fucosylated antibodies as more effective antitumor drugs than their fucosylated counterparts was a blockbuster. But realistically, there are challenges from a manufacturing point-of-view: all existing standard production procedures use production broths containing an enzyme that inevitably attaches fucose onto antibodies.
There are several ways to circumvent the situation. “For example, one can engineer cell lines that help make non-fucosylated antibodies, but it’s expensive. Also, it’s not very efficient because the cell line would be designed to produce one specific type of antibody,” says Britton. This means that for every antibody drug, there has to be a cell line engineered just for its production.
Britton, together with his collaborator Dr. David Vocadlo from Simon Fraser University, came up with an alternative solution. Instead of changing the production method completely, they proposed to add carbohydrate mimics—more specifically, fucose-like compounds—into the production broth. Because the fucose mimic is structurally similar to fucose, the enzyme is tricked into binding to the mimic and blocked for its normal activities, i.e. attaching fucose onto antibodies.
The advantage of the proposed solution is that these mimics could be used as a universal additive for the production of different antibodies. What’s more, the antibodies can be readily removed and harvested from the broth leaving behind these added mimics.
Despite their potential, the family of carbohydrate analogues Britton seeks after is not easy to make. His team has worked for years to develop methods that could make the synthesis of these analogues more cost-effective. With GlycoNet funding support since 2017, Britton says that his lab has successfully developed routes to synthesize a range of candidates. “We sent them first to our collaborator (Vocadlo), who has assays in-house to test these compounds’ ability to block fucosylation. From the testing results, we shipped several of them to a CRO to further test for their performance in the antibody production pipeline,” says Britton.
The team has discovered a promising lead from the panel of candidates. “We observed major reductions in fucosylation in the produced antibodies,” says Britton. Right now, the team is tweaking the structure of the lead to further increase its efficiency in blocking fucosylation. “There are a lot of trials and errors, and there is also the challenge of upscaling the synthesis of the candidates,” says Britton. Just like any other synthetic development, scaling up from milligrams to kilograms is not a simple, linear process. However, with the expertise and a track record in creating new molecules, Britton remains positive that the team will identify the best candidate and a convenient scale up to enable its production.