The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

  • LOG IN
  • BECOME A MEMBER
  • About
    • Mission & Activities
    • Directors and Officers
    • Marketing & Promotions
    • The Antibody Society’s Committees
      • Meetings Committee
      • AIRR Community Working Groups & Sub-Committees
    • Sponsors & Partners
  • Society meetings
    • Computational Antibody Discovery: State of the Art
      • Computational Antibody Discovery Symposium Participants
    • Harnessing Cytokines for Cancer Immunotherapy Symposium
    • Biopharmaceutical Informatics Symposium
    • Emerging Cancer Therapies Leveraging Gamma-Delta Effector T cells Symposium
    • Emerging Immunotherapeutics for Ovarian Cancer Symposium
    • AIRR Community Meetings
    • Antibody Engineering & Therapeutics (US) 2024
      • 2022 Antibody Engineering & Therapeutics
      • 2020 Antibody Engineering & Therapeutics
      • 2019 Antibody Engineering & Therapeutics
      • 2018 Antibody Engineering & Therapeutics
      • What is INN a Name?
        • INN issue updates
    • Antibody Engineering & Therapeutics Europe 10 – 12 June, 2025 | Congress Center, Basel Switzerland.
      • Scientific Advisors, Antibody Engineering & Therapeutics Europe
    • FOCIS Symposia
  • AIRR Community
    • AIRR Community News
    • AIRR Community Newsletter
    • AIRR Community Seminar Series
    • AIRR Community Meetings
      • Zooming into the Community III
      • AIRR Community Meeting VII – Learnings and Perspectives
      • AIRR Community Special Event 2023  – Zooming in to the Community II
      • AIRR Community Meeting VI: “Exploring New Frontiers”
      • AIRR Community Meeting V: “Zooming in to the AIRR Community”
      • AIRR Community Meeting V Pre-Meetings
        • AIRR-seq in the Pandemic
        • AIRR-seq Biological Standards and Workflows
      • AIRR Community Special Event: “Response to COVID-19”
      • AIRR Community Meeting IV: “Bridging the Gaps”
      • AIRR Community Meeting III
        • Day 1
        • Day 2
        • Day 3
        • Day 4
      • AIRR Community Meeting II
      • AIRR Community Meeting I
    • On AIRR – An AIRR Community Podcast
    • AIRR Data Commons
    • AIRR-C Germline Database Resources
    • AIRR Community Publications
    • AIRR Community Working Groups
      • Biological Resources Working Group
      • Common Repository Working Group
      • Diagnostics Working Group
      • Germline Database Working Group
      • Legal and Ethics Working Group
      • Software Working Group
      • Standards Working Group
    • AIRR Community Sub-Committees
      • Communications Sub-Committee
      • Executive Sub-Committee
      • Inferred Allele Review Committee
      • Meetings Sub-Committee
      • Strategic Planning Sub-Committee
    • AIRR Community Webinar Series
    • AIRR Community Calendar
    • AIRR Community Resources
  • Members only
    • Login
    • Note to members
    • Member discount codes
    • 2025 Calendar of Events
    • James S. Huston Antibody Science Talent Award
      • 2024 James S. Huston Antibody Science Talent Award Recipient
      • 2023 James S. Huston Antibody Science Talent Award Recipient
      • 2022 James S. Huston Antibody Science Talent Award Recipient
      • 2021 James S. Huston Antibody Science Talent Award Recipient
      • 2020 James S. Huston Antibody Science Talent Award Recipient
      • Huston Award submission guidelines
    • Research Competitions
      • Research Competition Winners
    • Science Writing Competition
      • Science Writing Competition Winners
    • Imaging Competition
      • Imaging Calendar Competition winners
        • The Antibody Society 2025 Calendar
        • The Antibody Society 2024 Calendar
    • Antibodies in early-stage studies
    • Presentations
  • Upcoming meetings in 2025
  • Web Resources
    • Society Publications
    • Antibody News
    • Antibody News Podcast
    • Antibody therapeutics approved or in regulatory review in the EU or US
      • Antibody therapeutics product data
    • Antibodies in late-stage clinical studies
    • Research Resources
    • Education Resources
  • Career Center
    • Career Shorts
  • Learning Center
    • Upcoming Webinars in 2025
    • The Antibody Series Lectures
    • Antibody Discovery & Development
    • Adaptive Immune Receptor Repertoires
    • Antibodies to Watch
    • Commercializing Antibody Therapeutics
    • Antibody Validation
      • 4th International Antibody Validation Meeting, Sep 2023
    • Snakebite antivenoms: Global challenges and progress toward recombinant antibody therapeutics
You are here: Home / Antibody Engineering & Therapeutics / Therapeutic Opportunities in Glycoscience: Bioorthogonal chemistry in translation

Therapeutic Opportunities in Glycoscience: Bioorthogonal chemistry in translation

December 29, 2022 by Janice Reichert

Lecture summary written by Czeslaw Radziejewski, PhD.

Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including Carolyn Bertozzi, Professor of Chemistry at Stanford University and 2022 Nobel prize laureate in Chemistry.

In her plenary lecture, Therapeutic Opportunities in Glycoscience: Bioorthogonal chemistry in translation, Prof. Bertozzi presented a retrospective of her remarkable contributions to chemical biology. She almost singlehandedly created the field of bioorthogonal chemistry, which is now used in the development of human biotherapeutics. Since its inception, bioorthogonal chemistry has had enormous scientific impact by enabling mechanisms to address a wide variety of biological questions.

Prof. Bertozzi was trained in traditional synthetic organic chemistry, but rapid advancements in biology inspired her to consider how chemical reactions might be reliably controlled within organisms. She started with the idea of performing chemical reactions in live cells. In contrast to organic synthesis, which is generally executed in organic solvents, often at high temperatures, chemistry done in live cells must occur in water at a pH close to physiological, at temperatures close to 37oC, and generally away from equilibrium. Carrying out reactions in living organisms is additionally complicated because the molecules used in-vivo cannot be toxic and cannot be metabolized faster than the reaction rate with a biological target. For such chemistry, Bertozzi coined the name and formulated the concept of bioorthogonal chemistry, which is chemistry that does not interact or interfere with a biological system. Bioorthogonal reagents and reactions must not have counterparts in biological systems. [1]

Prof. Bertozzi’s research focused on glycans, which are complex polysaccharides that decorate the surface of every mammalian cell. Notably, the structure and composition of glycans displayed on the cell surface undergo alterations in response to the physiological state of an organism. In normal cells, oligosaccharide structures terminate with the sialic acid, but it has been known since the 1960s that the glycosylation pattern on cancer cells is dramatically different from normal cells. Cancer cells tend to have a much higher abundance of sialic acids, which are attached to different sugars and in different linkages than in healthy cells. This difference in glycosylation architecture could potentially be exploited for imaging glycosylation using bioorthogonal chemistry. To begin with, the oligosaccharides would have to be labeled with a bioorthogonal sugar derivative bearing a functional group. In the next step, the functional group on the incorporated unnatural sugar would react with a bioorthogonal, detectable probe molecule. The early idea for a molecule that could be metabolically incorporated in place of sialic acid came from the work of a German carbohydrate chemist, Werner Reutter, who reported that N-acetyl-modified mannosamine could be used by cells as a precursor of side-chain modified sialic acid. Based on this observation, Bertozzi’s conceived the idea that the methyl group in the N-acetyl group could be appended with azide functionality. Then, a reactive, abiotic molecule could serve as the probe. Nucleophilic azide can enter a reaction called Staudinger reduction with triphenylphosphine, but this reaction results in azide reduction to a primary amine. However, when one of the phenyl rings was modified with an ester leaving group, hydrolysis of the transition product (azo-ylide) resulted in a stable linkage of the phosphine to sialic acid. The stable coupling of phosphine to azide group on a sugar moiety is known as Staudinger ligation.

Using Staudinger ligation, Prof. Bertozzi’s lab was able to demonstrate the remodeling of oligosaccharide architecture in living cells. [2] The slow kinetics and a requirement for a high concentration of phosphine limited the utility of this strategy, which prompted her to search for faster chemical, bioorthogonal transformations. Azides can also react with alkynes (Huisgen cycloaddition reaction) to produce triazoles. This reaction normally is also slow, but can be significantly accelerated by including copper(I) as a catalyst. This so-called click reaction was discovered by Barry Sharpless and Morten Meldal, who shared this year’s Nobel prize with Carolyn Bertozzi. However, due to its toxicity, copper (I) cannot be used in biological systems. The Husigen cycloaddition reaction can proceed much faster when the alkyne triple bond is a part of a strained ring structure. Based on this realization, Bertozzi’s lab synthesized strained cyclooctynes with tunable reactivity. During her presentation, Prof. Bertozzi showed a time-lapse video demonstrating how azido sugars and the strained difluorinated cyclooctyne were used to trace glycan redistribution during the early zebrafish embryogenesis. [3,4] Subsequently, a similar approach was used to visualize oligosaccharides in C. elegans, mice, plants, and in excised prostate cancer cells.

Bertozzi’s lab has also explored the significance of sialoglycan overexpression on cancer cells. It is now widely recognized that immune cells have both activating and inhibitory receptors on their cell surface, and that cancer cells that overproduce ligands for the inhibitory receptors can avoid detection and destruction by the immune system. Although antibody therapeutics that can block such immune checkpoints have been developed, many patients do not benefit from the therapy, suggesting the existence of other mechanism/s for cancer cells to evade immune system surveillance. Indeed, immunomodulatory sialic-acid-binding immunoglobulin-like lectins (Siglecs) that are expressed in hemopoietic and immune cells [5] can function as checkpoint receptors and promote immune evasion by cancer. There are 15 Siglecs in humans, and many of them use the same signaling pathways as the immune checkpoint PD-1. [6] Bertozzi’s lab, and subsequently many other groups, demonstrated that sialoglycans suppress immune cells via Siglecs signaling. Siglecs thus represent a potential new target for cancer therapy. Prof. Bertozzi noted that blocking Siglecs with monoclonal antibodies could be problematic because most immune cells have more than one Siglec. Therefore, her preferred strategy was to enzymatically remove excess of sialic acid from the surface of cancer cells with the enzyme sialidase. As a proof of concept, a fusion protein was created in Bertozzi’s lab using click chemistry, linking bacterial sialidase to the C-terminus of trastuzumab. [7] The conjugate was tested in a trastuzumab-resistant Her2+ breast cancer mouse model, which showed that the treatment essentially abrogated tumor growth. Based on these promising findings, Bertozzi cofounded Palleon Pharmaceuticals to explore sialidase-based biotherapies for cancer.

  1. Sletten E. and Bertozzi C. Angew. Chem.Int. Ed. 2009, 48,6974-98.
  2. Prescher J., Dube D. and Bertozzi C. Nature, 430, 873–877 (2004).
  3. Laughling S., Baskin J., Amacher S. and Bertozzi C. Science, 2008, 320, 664-7.
  4. Baskin J., Dehnert K., Laughlin S., Amacher S. and Bertozzi C. Proc Natl. Acad. Sci. USA. 2010,107, 10360-5.
  5. Bornhöfft K., Goldammer T., Rebl A. and Galuska S. Developmental & Comparative Immunology, 2018, 86, 219-231.
  6. Hudak J., Canham S. and Bertozzi C. Nat. Chem. Biol. 2014,10,69-77.
  7. Gray, M., Stanczak, M., Mantuano, N. et al. Nat Chem Biol. 2020,16,1376-1384.

Filed Under: Antibody Engineering & Therapeutics Tagged With: bioorthogonal chemistry, Carolyn Bertozzi

Share this post

  • LinkedIn

mabs

mabs

The Official Journal of The Antibody Society

Career Center

Our Career Center is a premier resource to connect highly qualified talent with matching career opportunities. Visit for details on over 800 jobs!

AIRR Community

AIRR Community

The Adaptive Immune Receptor Repertoire Community is a research-driven group organizing around the use of high-throughput sequencing technologies to study antibody/B-cell and T-cell receptor repertoires.

Recent Posts

  • Zooming into the Community III Starts Tomorrow! May 20, 2025
  • Exciting news – The AIRR Community is turning 10! 🎂 May 8, 2025
  • The Antibody Society (TAbS): Win a FREE Attendance Pass to AET Basel & Present A Poster: Call For Abstracts! March 26, 2025

Archives

Follow us online

  • Email
  • LinkedIn
  • Twitter
  • YouTube
  • Home
  • Privacy & Terms of Use
  • About
  • Directors and Officers
  • Advisors
  • Sponsors & Partners
  • Mission & Activities
  • Join the Society
  • Membership Levels
  • Members only
  • Login
  • Antibody therapeutics approved or in regulatory review in the EU or US
  • Meeting reports
  • Presentations
  • Contact

©2015 - scicomvisuals