In a groundbreaking study conducted by researchers from UCL and Stanford University, a potent anti-cancer therapy has been developed using Nobel prize-winning “click chemistry.” This innovative approach allows molecules to seamlessly connect, much like LEGO bricks, offering new opportunities for the development of cutting-edge cancer immunotherapies. The study, published in Nature Chemistry, showcases the creation of a three-component therapy targeting cancer cells. The therapy consists of a component that specifically targets cancer cells, another that recruits T cells to eliminate the cancer cells, and a third component that disrupts the cancer cells’ defenses. Traditionally, developing such therapies required complex protein engineering techniques, involving the combination of multiple proteins into a single cell using DNA sequences. However, the researchers demonstrated a more efficient method using click chemistry, which involves attaching “click handles” to proteins. This approach allows for the rapid testing of various combinations to identify the most effective therapy. The researchers successfully constructed a three-component therapy that employed an enzyme called sialidase to remove sugars that shield cancer cells. This particular therapy displayed remarkable effectiveness against breast cancer cells in laboratory dishes, indicating the enzyme’s potential as a foundation for the next generation of anti-cancer agents. Dr. Peter Szijj, the first author of the study, stated that click chemistry offers a quicker and adaptable approach compared to protein engineering. Furthermore, Professor Vijay Chudasama, the senior corresponding author, expressed their hope that the integration of click chemistry in the development of sophisticated multi-protein cancer therapies would inspire chemists to explore novel applications in medical imaging, diagnostics, and disease therapies. Click chemistry functions by enabling two reaction partners, known as click handles, to rapidly and selectively attach to each other without producing any toxic by-products. By incorporating functionalized pyridazinediones (PDs), the study’s researchers successfully attached click handles to proteins, allowing them to seamlessly “click” together, much like LEGO components. The pioneers of click chemistry were recognized with the 2022 Nobel Prize in Chemistry. Professor Carolyn R. Bertozzi from the University of Stanford, a co-author of the paper, received the Nobel Prize for her groundbreaking work on biorthogonal chemistry, specifically click chemistry in living cells. In this study, the UCL researchers first connected two antibody fragments using click chemistry—one fragment targeted cancer cells, while the other recruited T cells to destroy the cancer cells. Similar T cell engagers created through protein engineering have been approved for use in humans and are already being utilized to treat certain cancers, such as multiple myeloma. The researchers then introduced a third component, a checkpoint inhibitor, that disrupts the defenses of cancer cells. This component consisted of either a PD-1-blocking antibody fragment, which awakens immune cells to target cancer cells, or the experimental sialidase enzyme, which removes specific sugars on the cancer cell surface as well as on T cells. These sugars, abundant in cancer cells, enable them to evade the immune system by inactivating approaching immune cells. The addition of either component significantly enhanced the cancer-killing efficiency of the therapy, with sialidase exhibiting particularly potent effects. To visualize the binding efficiency of the therapy’s components, the researchers incorporated a fourth molecule, biotin. They noted that this molecule could be substituted with another small molecule serving a different purpose, such as masking the protein construct until it reaches the cancer cells to minimize side effects. The researchers believe that using chemistry to develop cancer therapies offers significant untapped potential for further exploration. However, before conducting human trials, the therapeutic containing the sialidase enzyme must be tested in animals. This exciting development in cancer treatment highlights the transformative potential of click chemistry and its role in revolutionizing future immunotherapies.
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