MedCity Influencers, BioPharma

What A Nobel Prize-Winner’s Research Means for Cancer Treatment

Drs. Carolyn Bertozzi, Barry Sharpless, and Morten Meldal shared the 2022 Nobel Prize in Chemistry for greatly simplifying the synthesis of complicated molecules. Dr. Bertozzi's protégé writes why her research is so important.

In October, Drs. Carolyn Bertozzi, Barry Sharpless, and Morten Meldal shared the 2022 Nobel Prize in Chemistry for greatly simplifying the synthesis of complicated molecules. Drs. Sharpless and Meldal are credited with the founding of click chemistry, which enables the joining of small modular units with biomolecules. Dr. Bertozzi took the principles of click chemistry to the next level to create the field of bioorthogonal chemistry, which is defined as click reactions that occur within living systems. Click chemistry reactions often rely on copper catalysts, but the toxicity of this metal prevents its use in the presence of live cells. By eliminating copper, Dr. Bertozzi was able to modify molecules in living organisms without interfering with normal cell functions.

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

Dr. Bertozzi’ findings have significant implications for the treatment of cancer. There had been over 50 scientific papers published – the earliest ones dating back to the 1960s – that demonstrated a positive correlation between higher density of sialoglycans on the surfaces of tumor cells and worse clinical outcomes for 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 terminate 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 had identified a glyco-immune checkpoint – analogous to the PD-1 checkpoint – that could be targeted for drug development. Her efforts have catalyzed the glyco-immunology field– an emerging field that addresses how glycans regulate and direct the body’s immune response. Glyco-immunology drug development has the potential to produce novel therapeutics to treat cancer, inflammatory disorders, and other serious diseases.

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

Beyond checkpoint inhibitors, approaches including non-specific immunotherapies that support the immune system in destroying cancer cells, oncolytic virus therapy that utilizes viruses altered within labs to destroy cancer cells, T-cell therapies, and cancer vaccines have all been studied and garnered approvals from the FDA.

There is no doubt that these immunotherapy options have had meaningfully improved outcomes for many patients, however, the majority of cancer patients do not respond to medicines that are available today. It is possible that the glyco-immune axis of regulation holds the key to understanding resistance to current therapies. As researchers began to interrogate this newly discovered axis, they focused initially on blocking the Siglec receptors. Research made it clear that the biology was highly redundant, and it was discovered that targeting a single Siglec receptor or one of its ligands would not be an effective means of drugging this immune checkpoint. In 2016, Dr. Bertozzi and colleagues experimented with an alternative approach to targeting this axis of immunosuppression. They chemically fused a recombinant sialidase enzyme to a tumor antigen-targeted antibody to create an enzyme-antibody conjugate that was shown to enhance immune cell activation by desialylating tumor cells. By stripping the 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 that was 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 have taken chemistry into the era of functionalism. This is bringing the greatest benefit to humankind.” Immense progress has been made in the treatment of serious diseases like cancer, but there is plenty of work to be done. Dr. Bertozzi’s work has paved the way to develop innovative treatments for millions of people suffering from cancer and other serious diseases whose needs are not met by today’s medicines. I’m optimistic that we can make great strides for patients with this novel approach to drug development.

 


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Li Peng

Li Peng has over 15 years of industry experience in drug discovery and development. Since joining Palleon at its launch in 2016, she has led the invention of Palleon’s EAGLE, CONVERGENCE and HYDRA platforms and overseen research and early development, including discovery, pharmacology, toxicology, and CMC. Previously, Li worked at Medimmune/AstraZeneca for 10 years in roles of increasing responsibility, leading drug discovery programs and cross-functional project teams. She has published over 30 scientific papers and is an inventor on ~20 patents and patent applications. Li earned a B.S. in biology from Capital Normal University, Beijing, and a Ph.D. in biochemistry and molecular biology from the University of California, Davis.

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