Targeting sugar molecules: Can glycobiology lead to a new era for cancer immunotherapy?

As the biotech industry always searches for new types of therapies that can improve on current standard-of-care treatments, glycobiology is now emerging as an area that could potentially lead to a new type of cancer immunotherapy and become an alternative approach to using conventional immune checkpoint inhibitors, a type of drug that continues to face numerous challenges. In this article, we take a look at what glycobiology is, how it can be applied to cancer immunotherapy, and which companies are currently operating in the up-and-coming field of glyco-immunology. 

Finding new checkpoints with glycobiology: An emerging approach to cancer immunotherapy

In its broadest sense, the term glycobiology refers to the study of the structure, function, and biology of carbohydrates, also known as glycans, which are essentially sugar molecules that are present in every living organism and have long been known to play major metabolic, structural, and physical roles in biological systems.

Glycans also happen to act as important immune system communicators and play a pivotal role in regulating immune response. Certain glycans, known as “glyco-immune checkpoints”, act as receptors on immune cells that normally distinguish “self” from “non-self” cells (the body’s own cells are recognized as “self” cells, while cells that do not originate in the body are “non-self” cells). However, these checkpoints can become exploited in cancer to create immunosuppression that ultimately allows tumors to thrive. 

By developing drugs that target these glyco-immune checkpoints, in one way or another, biopharma companies can modulate them, helping the body’s immune system identify and attack cancer cells. 

This is a similar concept to traditional immune checkpoint inhibitor drugs, which usually work by blocking PD-1, a receptor that sits on the surface of killer T cells, or its ligand PD-L1; if PD-1 binds to PD-L1, which is overexpressed on the surface of some cancer cells, the tumor cell can evade detection. But immune checkpoint inhibitors are flawed. They only work on a fairly small percentage of people – a recent study estimated that, as a best-case estimate, up to 12.5% of patients respond to them. 

In 2017, Jim Broderick, chief executive officer (CEO) and founder of glyco-immunology startup Palleon Pharmaceuticals, told Fierce Biotech: “When first-generation T-cell checkpoint inhibitors work, they work extremely well, but unfortunately the majority of patients still do not respond. This is because most tumors utilize multiple strategies to thwart the immune system, and T-cell checkpoint inhibition is insufficient to drive a response alone.”

He continued to explain, however, that glyco-immune checkpoints are expressed on a broader range of innate and adaptive immune cells critical to an antitumor response compared to other targets, meaning that targeting them “offers the potential to awaken a broader spectrum of the immune system in tumor types that are not responsive to first-generation immuno-oncology drugs.”

Palleon Pharmaceuticals: Leading the way in glycobiology field 

Launched in July 2015, Palleon Pharmaceuticals has been working in the glycobiology field for a few years now after the company licensed intellectual property related to glycoimmune checkpoints from its co-founders Carolyn Bertozzi, a Stanford University scientist who won the Nobel Prize in chemistry in 2022 for her work on bioorthogonal chemistry, and Paul Crocker, of Dundee University in the U.K. 

Its work is built on decades of research that has shown that some glycan patterns on tumor cells, particularly a motif known as “hypersialylation,” are associated with poor clinical outcomes. Essentially, tumor cells hide from the immune system by altering their glycan coat. Compared with healthy cells, cancer cells sport a higher density of glycan structures terminating in sialic acid, the ligand for sialic acid-binding immunoglobulin-like lectins (Siglecs). Bertozzi reasoned that targeting these Siglecs or their sialic acid ligands could yield new immune therapies to expand the therapeutic reach of the current batch.

Palleon’s EAGLE platform enables the development of therapeutics that strip sialic acid from both cancer cells and immune cells, enabling immune cells to launch a comprehensive antitumor response with immune memory. The platform is based on engineered human sialidase enzymes, and Palleon is developing targeted sialidase molecules comprising a human sialidase enzyme and a targeting arm that can restore antitumor immunity by enzymatically degrading immunosuppressive sialoglycans on hypersialylated tumors and immune cells.

In April 2023, Palleon announced phase 1 results from the GLIMMER-01 trial to evaluate its lead candidate in oncology, E-602 as a monotherapy, demonstrating proof of mechanism, including dose-dependent desialylation and dose-dependent immune system activation. Additionally, E-602 was found to be well tolerated across the entire dose range evaluated with no dose-limiting toxicities.

Most recently, in November 2024, Palleon also announced positive results from a phase 1/2 trial of E-602 in combination with the PD-1 checkpoint inhibitor cemiplimab in patients with PD-(L)1-resistant solid tumors, including melanoma, non-small cell lung cancer, and esophagogastric junction cancer. All the patients were assessed for tumor sialoglycan levels and characterized as having hypersialylation or not. The drug combination was found to be generally well-tolerated, with no dose-limiting toxicities observed, and patients with tumor hypersialylation trended toward better clinical outcomes compared to those lacking hypersialylation, including a confirmed partial response achieved in one anti-PD-1 resistant melanoma patient, and disease stabilization achieved in another six patients.

Valora Therapeutics emerges with $30 million to advance glyco-immune checkpoint platform 

Just last month, Valora Therapeutics emerged from stealth with $30 million in seed financing, providing the company with the opportunity to advance its glyco-immune checkpoint platform, AbLec, to develop novel immunotherapies.

The company’s platform is based on the fact that glycans form a crucial part of the “sugar code,” a language that cells use to communicate with the immune system, by modulating lectin receptors, including Siglec receptors, expressed on immune cells. As this glycan code is disrupted in cancer, Valora’s approach is to design molecules that normalize the glyco-immune signaling at the pathological cell, providing cell specificity and avoiding deregulation of physiologically relevant glycan-lectin interactions in healthy tissue. 

“Immune cells are all the time patrolling in the body and trying to detect something that is abnormal and destroy it,” Miguel Garcia-Guzman, CEO of Valora, told Biopharma Dive. “Nobody has figured out so far how to restore the proper communication of the sugar molecules in cancer in [such] a way [that] you can rebuild immune anti-cancer competency. That’s the new mechanism we’re trying to address with our own technology.”

Known as antibody-lectin chimeras, or “AbLecs”, Valora’s immunotherapies look much like a conventional antibody, but with one of the usual Y-like arms replaced with a lectin domain. While the antibody domain provides precise targeting to specific cells or tissues, the lectin domain binds to glycans to either reduce or activate their signaling.

Valora’s technology is exclusively licensed from Stanford University and, like Palleon, is built on the research conducted by Carolyn Bertozzi, as well as Jessica Stark, a Massachusetts Institute of Technology researcher in biological and chemical engineering, both of whom are scientific founders and advisers to Valora.

The company will now use the seed funding it raised to develop its AbLec platform and launch preclinical studies.

Can glycobiology also be applied to other therapeutic areas?

Although primarily useful for cancer treatment, it seems that glycobiology also holds potential in other disease areas. In fact, both Palleon and Valora are looking to develop glyco-immune drugs for autoimmune diseases, too. 

According to Palleon, changes in cell surface glycosylation – defined as a post-translational modification involving the addition and extension of carbohydrates on proteins and lipids – can also contribute to immune dysfunction in inflammatory and autoimmune diseases, and targeting sialoglycans and/or their receptors could have therapeutic potential in suppressing the immune system in these diseases. In addition, targeting sialoglycan biology in combination with other agents could address refractory autoimmunity in some patients. Palleon is developing multiple strategies, including glycan-editing and Siglec-targeting programs to address this therapeutic area.

Meanwhile, Valora believes that the disruption of the glycan-lectin interactions that it is targeting for cancer also results in defective immune control in inflammatory diseases. Using its AbLec platform, the company wants to precisely modulate specific immune cell subsets to restore immune balance and reduce autoimmune responses, ultimately creating new targeted therapies with potentially fewer side effects than current broad-spectrum immunosuppressants.

Another company, Aviceda Therapeutics, is also making use of glycobiology, with its lead program, AVD-104, currently focusing on ophthalmology – specifically geographic atrophy, a late stage of macular degeneration. The company completed the enrollment of a phase 2b trial in September 2024 to assess the safety and efficacy of AVD-104 in this indication. 

AVD-104 is essentially a glycan-coated nanoparticle with a dual mechanism of action that modulates critical inflammatory cellular and complement pathways. 

Like Palleon, Aviceda has a focus on Siglecs. Its nanotechnology platform, HALOS, (High-Affinity Ligands of Siglecs) synthesizes ligands that have greater binding affinity to Siglecs than nature’s cell-derived ligands, antibodies, or other small molecules. Aviceda’s molecules are basically immune cell engagers, with the ability to specifically target different immune cells with precision. 

The company also has a pipeline of candidates for fibrosis, immunology, neurology, and oncology but these are still either in the discovery, preclinical, or Investigational new drug (IND)-enabling phase. 

The rising focus on glycobiology: A contributing factor to expected glycomics market growth

According to Grand View Research, the global glycomics market size was valued at $1.65 billion in 2022 and is expected to grow at a compound annual growth rate (CAGR) of 14.6% from 2023 to 2030. 

One of the main contributing factors to this growth is the rising focus on glycobiology research. Grand View Research noted that the glycobiology field has gained significant momentum in recent times owing to its numerous applications in various areas, including diagnostics, drug discovery, and personalized medicine. Moreover, increasing interest in understanding the role of glycomics in disease profiling and biological processes has significantly fueled the research & development (R&D) activities in the area of glycomics. 

So, as Palleon takes its lead candidate through the clinic and Valora sets out on preclinical work and develops its technology platform, the field of glycobiology could begin to gain even more traction, ushering in an entirely new era in cancer immunotherapy.

New technologies related to glycobiology

• Dendritic Cell-based Therapies for Cancer Treatment – Universidade NOVA de Lisboa
• Sn2 Glycosylation Suitable For Automated Glycan Synthesis – University of California, Santa Barbara
• A Platform for High-Resolution Phenotyping of Cells for Functional Characterization, Enrichment and Targeting – Albert Einstein College of Medicine