What Nobel Prize-winning research means for cancer treatment - MedCity News
What Nobel Prize winning research means for cancer treatment  ,  in October Dr. Carolyn Bertozzi, Barry Sharpless and Morten Meldahl shared Nobel Prize in Chemistry 2022 to greatly simplify the synthesis of complex molecules. Drs. Sharpless and Meldahl are credited with founding click chemistry, which allows the attachment of small modular units to biomolecules. Dr. Bertozzi took the principles of click chemistry to the next level to create the field of bioorthogonal chemistry, which is defined as the click reactions that occur in living systems. Chemical click reactions often rely on copper catalysts, but the toxicity of this metal prevents its use in the presence of living cells. By eliminating copper, Dr. Bertozzi was able to modify molecules in living organisms without interfering with normal cellular functions.

Dr. Bertozzi’s work has spawned the creation of several biopharmaceutical companies, including Palleon Pharmaceuticals(where I work) Thios Pharmaceuticals, Redwood Bioscience, Enable Biosciences, InterVenn Biosciences, Lycia Therapeutics and Olilux Biosciences. Her revolutionary scientific discoveries have contributed to new ways of treating very serious diseases that affect millions of people.

Dr. Bertozzi’s findings have significant implications for cancer treatment. More than 50 scientific papers have been published – the earliest dating back to the 1960s – demonstrating a positive association between a higher density of sialoglycans on tumor cell surfaces and worse clinical outcomes in cancer patients. However, the mechanism that protects these tumors from the body’s immune response to cancer was unknown. Using tools enabled by bioorthogonal chemistry, she demonstrated that sialoglycans—which are glycans that end with a sugar building block called sialic acid—are immunosuppressive in cancer.

This discovery shed light on an important axis of immune regulation, and Dr. Bertozzi identified a glyco-immune checkpoint—analogous to the PD-1 checkpoint—that could be targeted for drug development. Her efforts have catalyzed the field of glycoimmunology, an emerging field that deals with how glycans regulate and direct the body’s immune response. Glycoimmunological drug development has the potential to produce novel therapeutics for the treatment of cancer, inflammatory diseases, and other serious diseases.

The the immunotherapy landscape has seen significant progress over the past few years, with several effective treatments approved and available to patients. Most options that use this approach stem from treatments targeting the CTLA-4 and PD-1/PD-L1 pathways, a discovery that was also recognized with the 2018 Nobel Prize for Dr. James Allison and Dr. Tasuka Honjo. Over the past decade, the FDA has approved several immune checkpoint inhibitors targeting these pathways, including atezolizumab (Tecentriq), durvalumab (Imfinzi), ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo).

In addition to checkpoint inhibitors, approaches including nonspecific immunotherapies that support the immune system in destroying cancer cells, oncolytic viral therapy that uses viruses modified in laboratories to destroy cancer cells, T-cell therapies, and cancer vaccines all have been studied and received FDA approvals.

There is no doubt that these immunotherapy options have greatly improved outcomes for many patients, but the majority of cancer patients do not respond to the drugs available today. It is possible that the glyco-immune axis of regulation holds the key to understanding resistance to current therapies. When researchers began interrogating this newly discovered axis, they initially focused on blocking Siglec receptors. The research made it clear that the biology was very redundant and it was discovered that targeting a single Siglec receptor or one of its ligands would not be an effective means of anesthetizing this immune checkpoint. In 2016, Dr. Bertozzi and colleagues experimented with an alternative approach to target this axis of immunosuppression. They chemically fused a recombinant sialidase enzyme with an antibody targeting a tumor antigen to create an enzyme-antibody conjugate that was shown to enhance immune cell activation by desialylating tumor cells. By removing terminal sialic acids from the glycans that cover the surfaces of cancer cells and immune cells, the glyco-immune checkpoint axis is released and antitumor immunity is restored. The first drug candidate developed using this technology is now being administered to patients in a clinical trial.

Dr. Bertozzi’s groundbreaking discoveries have the potential to significantly impact the immunotherapy landscape. As stated so eloquently by the Royal Swedish Academy of Sciences, “Click chemistry and bioorthogonal reactions ushered chemistry into the era of functionalism. It is of the greatest benefit to humanity.” Tremendous progress has been made in the treatment of serious diseases such as cancer, but there is much work to be done. Dr. Bertozzi’s work paved the way for the development of innovative treatments for millions of people suffering from cancer and other serious diseases whose needs are not met by today’s drugs. I am optimistic that we can make great strides for patients with this new approach to drug development.

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