Palleon Pharmaceuticals Showcases First-in-Class B7-H3–Targeted Sialidase at AACR 2026
Palleon Pharmaceuticals has unveiled new preclinical findings and announced the initiation of a first-in-human clinical trial for its novel oncology candidate E-688/HLX316 during the American Association for Cancer Research Annual Meeting. The data were presented as part of the highly regarded “New Drugs on the Horizon” session, highlighting emerging therapies with the potential to redefine cancer treatment paradigms. The presentation introduced E-688/HLX316 as a first-in-class, tumor-targeted enzymatic therapy designed to overcome a key mechanism of immune evasion in cancer.
At the core of Palleon’s approach is the targeting of tumor hypersialylation, a biological phenomenon characterized by the overexpression of sialic acid-containing glycans on the surface of cancer cells. This process plays a crucial role in helping tumors evade the immune system. By engaging multiple sialic acid-dependent immune regulatory pathways, hypersialylation effectively suppresses both innate and adaptive immune responses, allowing tumors to grow and spread unchecked. Importantly, this mechanism of immune escape has been observed across a wide range of solid tumors and has been consistently associated with poor clinical outcomes in numerous studies.
Despite its significance, tumor hypersialylation has historically been difficult to target using conventional therapeutic approaches. Traditional modalities such as monoclonal antibodies and small molecule drugs have limited ability to disrupt the complex and redundant glycan-mediated pathways involved in this form of immune suppression. Recognizing this challenge, Palleon has developed a novel strategy centered on enzymatic desialylation—the removal of sialic acid molecules directly from the tumor surface.
E-688/HLX316 represents the company’s most advanced effort in this area. It is engineered as a B7-H3-targeted sialidase, combining tumor-specific targeting with enzymatic activity. The B7-H3 protein is widely expressed on many tumor types, making it an attractive target for selective delivery. Once bound to the tumor, the sialidase component of the molecule enzymatically cleaves sialic acid residues, effectively dismantling the protective glycan shield that tumors use to suppress immune activity. This mechanism is designed to restore immune recognition and enhance the body’s natural ability to attack cancer cells.
The development of E-688/HLX316 builds upon earlier work with Palleon’s first-generation sialidase, E-602. In prior clinical studies, E-602 demonstrated proof-of-mechanism in humans, showing that enzymatic desialylation could be achieved safely and with a favorable tolerability profile. That program has since progressed into Phase 2 development for autoimmune diseases, providing valuable clinical insights into the behavior of sialidase-based therapies in humans.
However, oncology applications present additional challenges and requirements. Effective cancer therapies must not only modulate the immune environment but also achieve sustained activity within the tumor and, ideally, exert direct anti-tumor effects. Lessons learned from E-602 informed the design of E-688/HLX316, which was specifically engineered to deliver durable, tumor-localized desialylation while also enhancing cytotoxic activity against cancer cells.
Preclinical data presented at AACR 2026 support the effectiveness of this approach. In in vivo models, E-688/HLX316 demonstrated the ability to maintain desialylation of the tumor surface for more than seven days, a significant improvement in durability compared to earlier approaches. This prolonged activity is critical for sustaining immune activation and maximizing therapeutic impact. Furthermore, in humanized tumor models, the agent outperformed therapies targeting the PD-1/PD-L1 pathway when used as a single agent, suggesting that it may offer a distinct and potentially complementary mechanism of action.
The data also showed that E-688/HLX316 enhances both innate and adaptive immune responses. By removing sialic acid-mediated inhibitory signals, the therapy enables immune cells such as macrophages and natural killer cells to more effectively recognize and attack tumor cells, while also supporting the activation of T cells. This dual impact is particularly important in the context of immuno-oncology, where combination strategies and multi-faceted immune engagement are increasingly seen as key to achieving durable responses.
According to Palleon’s leadership, these findings validate tumor hypersialylation as a clinically actionable target and demonstrate that enzymatic desialylation can successfully disrupt this axis of immune evasion. The company believes that this approach operates independently of traditional immune checkpoint pathways, offering new opportunities for patients who may not respond to existing immunotherapies.
Building on this strong preclinical foundation, E-688/HLX316 has now entered clinical development. The first-in-human trial is being conducted in patients with platinum-resistant ovarian cancer, a population with significant unmet medical need and limited treatment options. The study is taking place in China and is being led by Palleon’s strategic partner Henlius, reflecting a collaborative approach to advancing the therapy globally.
The choice of ovarian cancer as the initial indication is strategic, as these tumors often exhibit high levels of hypersialylation and immune suppression. By targeting this biology directly, E-688/HLX316 has the potential to improve outcomes in a setting where current therapies frequently fall short. The trial will evaluate the safety, tolerability, and preliminary efficacy of the therapy as a monotherapy, providing critical insights into its clinical potential.
Looking ahead, Palleon plans to expand the clinical development of E-688/HLX316 into additional tumor types characterized by high expression of B7-H3 and significant hypersialylation. These include major cancers such as lung and prostate cancer, where the need for more effective immunotherapies remains substantial. The company’s broader strategy is to systematically explore the utility of its sialidase platform across multiple indications, potentially establishing a new class of cancer therapeutics.
The announcement at AACR 2026 underscores the growing interest in novel mechanisms of immune modulation beyond traditional checkpoint inhibition. As the field of oncology continues to evolve, approaches that target previously untapped pathways—such as glycan-mediated immune suppression—are gaining attention for their potential to complement existing therapies and address unmet needs.
In summary, Palleon Pharmaceuticals’ introduction of E-688/HLX316 marks an important milestone in the development of next-generation immunotherapies. By leveraging enzymatic desialylation to counteract tumor hypersialylation, the company is advancing a fundamentally new strategy to enhance anti-tumor immunity. With promising preclinical data and a clinical trial now underway, E-688/HLX316 represents a significant step forward in the effort to unlock new therapeutic possibilities for patients with cancer.
About Palleon Pharmaceuticals
Palleon Pharmaceuticals is a clinical-stage biotherapeutics company developing first-in-class engineered sialidase therapies for the treatment of cancer and autoimmune disease. Co-founded on the glycobiology research of Carolyn Bertozzi (2022 Nobel laureate in Chemistry), Palleon is the first company to translate this science into human therapeutics targeting cell surface sialoglycans. Palleon’s platform has generated two clinical programs: E-602 (Phase 2, membranous nephropathy) and E-688/HLX316 (first-in-human, platinum-resistant ovarian cancer). www.palleonpharma.com
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