Nobel Laureate Carolyn Bertozzi: Glycans, Cancer, and Bioorthogonal Chemistry

Carolyn Bertozzi's Research Focus

• 💡 Dr. Carolyn Bertozzi, a Nobel Prize laureate in Chemistry (2022), is recognized for pioneering bioorthogonal chemistry.
• 🔬 Her work at Stanford's ChEM-H Institute combines diverse scientific fields to study life at the molecular level for improving human health.
• 🎯 While bioorthogonal chemistry was the means, her ultimate goal has always been to study the biology of sugars, specifically glycans.

The Significance of Cell Surface Sugars

• 🌱 All cells, across nearly all organisms, are coated with complex carbohydrates called glycans (or the glycocalyx).
• 💬 These glycans form a language for cells to communicate their status to the outside world, with different patterns indicating different cell types or developmental stages.
• 🩸 A well-known example of glycan importance is blood type determination, where specific sugar structures on red blood cells dictate A, B, or O types, crucial for safe blood transfusions.

Cancer's Glycan-Based Immune Evasion

• ⚠️ For over 50 years, it's been known that cancer cells have altered glycan patterns, often showing an overproduction of P-sialic acid.
• 🛡️ The immune system's T-cells normally patrol the body, identifying and eliminating abnormal cells by sampling their surface molecules.
• 😴 Cancer cells exploit this system by using the dense P-sialic acid coating to bind to SIGLEC receptors on immune cells, effectively putting the immune cells "to sleep" and evading destruction.

Developing New Glycan-Targeted Cancer Therapies

• 🚀 Traditional immunotherapies block checkpoint receptors (like PD1), but many cancers don't respond, suggesting other immune evasion mechanisms are at play.
• 🛠️ Bertozzi's lab developed a novel approach: "cancer-targeted lawnmowers"—antibody-sialidase conjugates—designed to strip P-sialic acid from cancer cells.
• ✅ These molecular lawnmowers, created using bioorthogonal chemistry, showed promising results in mouse models, leading to the destruction of cancer cells and the development of immunological memory.

Bioorthogonal Chemistry and Future Outlook

• 🧪 Bioorthogonal chemistry enables chemical reactions to occur within living systems without interfering with native biological processes, making it ideal for creating complex drug conjugates.
• 📈 The initial prototypes, using bacterial enzymes, have been re-engineered by Palleon Pharmaceuticals into the EAGLE platform, utilizing a human sialidase for improved drug-likeness.
• ⏳ This new drug is slated for first-in-human clinical trials by mid-2026, with hopes of providing new therapeutic options for cancer patients, either alone or in combination with existing immunotherapies.