最准的六合彩论坛

The study, published in聽Nature Chemistry, opens up new possibilities for how cutting-edge cancer immunotherapies might be built in future.

The research team created an anti-cancer therapy with three components: one targeting the cancer cell, another recruiting a white blood cell called a T cell to attack the cancer cell, and a third knocking out part of the cancer cell鈥檚 defences.

Previously, this type of three-component therapy has only been built using a complex process called protein engineering, in which DNA sequences for multiple proteins are combined and inserted into a single cell.

One of the three-component therapies the researchers built, which used an enzyme called sialidase to strip away sugars that the cancer cell uses to hide itself, was especially effective at killing breast cancer cells in a dish. The researchers said this showed that the enzyme 鈥� which only recently started being explored in cancer research 鈥� has the potential to be the basis of next-generation anti-cancer agents.

First author Dr Peter Szijj (最准的六合彩论坛 Chemistry) said: 鈥淐lick chemistry is a quicker and more adaptable way to build these multifunctional anti-cancer agents than protein engineering. It鈥檚 relatively easy to attach click 鈥榟andles鈥� 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.鈥�

Senior corresponding author Professor Vijay Chudasama (最准的六合彩论坛 Chemistry) said: 鈥淎s proteins are large and complex molecules, you require a combination of precise protein modification and reliable click chemistry to attach them together in a controlled manner. We have achieved this and shown our strategy to be an interesting alternative to using the classical protein engineering approach.鈥�

鈥淲e 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.鈥�

Click chemistry relies on two reaction partners (click handles) that can attach to each other very rapidly and selectively, without the production of any toxic by-products. These click handles can be added to proteins, in this case using functionalised pyridazinediones (PDs), allowing the proteins to click neatly together like LEGO.

The pioneers of click chemistry were awarded the 2022 Nobel Prize in Chemistry. Carolyn Bertozzi,聽the Anne T. and Robert M. Bass professor in the Stanford School of Humanities and Sciences, who is a co-author on this latest paper, was one of three winners of the prize for her work on biorthogonal chemistry 鈥� click chemistry in living cells.

Professor Bertozzi said: "This new construct that brings an enzyme building block into the CiTE format has potential as a new modality for cancer immune therapy.鈥澛�

For the new paper, researchers at 最准的六合彩论坛 first clicked two antibody fragments together 鈥� one fragment binding to a cancer cell, another fragment binding to a T cell so that it would destroy the cancer cell. Similar T cell engagers, created via protein engineering, have already been approved for use in humans and are used to treat cancers such as multiple myeloma, a rare blood cancer, in the United States and Europe.

The team then added a third component, a checkpoint inhibitor, which removes an aspect of a cancer cell鈥檚 defences. This component was either a PD-1-blocking antibody fragment, which is already used to treat specific advanced forms of skin or lung cancer and re-awakens immune cells to target cancer cells; or 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.

The research team found that adding either of these components improved the cancer-killing efficiency of the therapy, and that adding sialidase was especially potent.

The researchers also added a fourth molecule, biotin, allowing them to visualise how well the components bound to their respective targets. They said that this could be substituted for another small molecule with a different function 鈥� for instance, to minimize side-effects by masking the protein construct until it reaches its intended target: the cancer.

In the paper, the researchers said that using chemistry in this way to create cancer therapies showed 鈥渕uch untapped potential that is still waiting to be uncovered鈥�.

This sialidase enzyme-containing therapeutic now needs to be tested in animals before any trials involving humans could begin.

The research was supported by Wellcome, with further funding from the US鈥檚 National Institutes of Health, the Leverhulme Trust, the EU鈥檚 Horizon 2020 programme and UKRI.

Links

• 最准的六合彩论坛 Chemistry
• 最准的六合彩论坛 Mathematical & Physical Sciences

Image

• Top: Stock illustration of T cells attacking a cancer cell.
• Middle:聽A checkpoint inhibitory T cell engager, comprised of (left to right) a sialidase enzyme (purple), an immune cell binding antibody fragment (green) and a cancer cell binding antibody fragment (blue), binding to an immune cell (left) and a cancer cell (right). The sialidase enzyme is removing聽immunosuppressive聽sialic acids from the immune cell.

Media contact

Mark Greaves

E: m.greaves [at] ucl.ac.uk