Nobel Prize laureate Carolyn Bertozzi and researchers from Stanford and University College London have leveraged the prize-winning chemistry method she helped pioneer to create a potent anti-cancer therapy. The new click chemistry-based therapy is simpler, quicker and more efficient than protein engineering, the previous gold standard process.
Last year, Bertozzi was awarded the 2022 Nobel Prize in Chemistry for her part in the development of click chemistry and bioorthogonal chemistry. Click chemistry is a form of simple and reliable chemistry where reactions occur quickly and unwanted byproducts are avoided. The method relies on two reaction partners—or click handles—that attach to each other rapidly and selectively. These click handles can be added to proteins, allowing the proteins to “click” neatly together—like LEGOs.
In 1997, Bertozzi became the first scientist to introduce click chemistry in living creatures—something not even K. Barry Sharpless, the father of the technique, thought was possible. She then continued to refine her reactions to ensure they would work even better in cell environments.
Bertozzi—and now many other scientists—have used these reactions to explore how biomolecules interact in cells and study disease processes. This newest research is another step in that direction, opening new possibilities for how cutting-edge cancer immunotherapies might be built in the future.
Clicking into place
In the latest study, researchers at University College London first clicked two antibody fragments together—one fragment binding to a cancer cell, another binding to a T-cell so that it would destroy the cancer cell.
According to the paper, published in Nature Chemistry, the researchers also added two different fragments as the third component. One was a PD-1-blocking antibody fragment, which is already extensively used to treat specific advanced forms of skin or lung cancer. The other was the more experimental sialidase enzyme, which strips away specific sugars (sialic acids) on the surface of the cancer cell, as well as on the T-cell. These sugars, present on all our cells, are produced in large amounts by cancer cells and help them to hide from our immune system by switching off approaching immune cells.
Both components improved the cancer-killing efficiency of the new therapy, but adding sialidase was especially potent. Additionally, compared with protein engineering, the click chemistry-based therapy was shown to be optimal.
“Click chemistry is a quicker and more adaptable way to build these multifunctional anti-cancer agents than protein engineering. It’s relatively easy to attach click ‘handles’ to proteins so you can try lots of combinations quickly to test what might work best. Using protein engineering, you need a separate mechanism for each component,” said first author Peter Szijj, chemistry professor at University College London.
The scientists also added a fourth molecule, biotin, to visualize how well the components bound to their respective targets. And while that worked well for the study purposes, importantly, the researchers say biotin can easily be substituted for another small molecule with a different function. For example, one that helps to minimize side effects by masking the protein construct until it reaches its intended target.
Next, the sialidase-based therapeutic will be tested in animals, before any trials involving humans can begin.
“We hope that by using chemistry to create novel and highly sophisticated multi-protein anti-cancer agents we can inspire chemists to cross the typical boundaries of the discipline to engage in novel applications in areas such as medical imaging, diagnostics and disease therapies,” said senior corresponding author Vijay Chudasama, professor of chemistry at University College London. “There is much untapped potential that is still waiting to be uncovered.”