Just as the recombinant DNA technology of the 1970s enabled the birth of biotechnology, research tools developed and refined in the early 21st century have opened a drug discovery frontier centered around glycans, the sugar molecules that coat cell surfaces.
Palleon is transforming these discoveries into therapeutics designed to manipulate glycans and their receptors to treat a wide variety of serious conditions. Leveraging our unrivaled scientific expertise and our proprietary platform technologies, Palleon is uniquely positioned to realize the potential of the glycobiology revolution for patients.
Sialoglycans’ Role in Immune Regulation
Sialoglycans are biomolecules that contain one or more carbohydrate chains and
terminate with sialic acids.
Sialoglycans are the central node in a highly redundant immunosuppressive network that identifies human cells as “self.” A broad array of immune cells — including dendritic cells, macrophages, natural killer cells, and T cells — have sialoglycan-sensing receptors that block immune activation when they encounter a sufficient density of sialoglycans.
Changes in sialylation are a major driver of immune dysfunction in many diseases. For example, upregulation of sialoglycans on both cancer cells and immune cells results in immune suppression. Downregulation of sialoglycans removes this suppression of the immune system, making “self” tissue vulnerable to autoimmunity.
Hypersialylation of tumors and T cells results in pan-immune suppression and immune escape. Decades of research have demonstrated that the upregulation of sialoglycans on tumor cells is correlated to poor clinical outcomes. Palleon’s research shows that sialoglycans are upregulated on exhausted T cells, which suppresses T-cell function.
Sialoglycan-mediated immune suppression in cancer cannot be targeted with conventional approaches due to the redundancy of the receptors and the vast number of sialoglycan ligands. Palleon’s EAGLE platform enables the development of therapeutics that strip sialic acids — the critical and common dependency of this axis — from both immune cells and cancer cells. Desialylation of both tumors and immune cells enables innate and adaptive immune cells to target the tumor, resulting in a pan-immune response with adaptive memory.
Palleon’s lead candidate, E-602 (Bi-Sialidase) removes sialic acids on both T cells and tumor cells, potentiating an anti-tumor immune response. Palleon is also developing tumor associated antigen-targeted sialidase molecules that enable more efficient desialylation of tumor cells.
Palleon has pioneered a novel strategy to reverse the immunosuppressive effects of sialoglycans by enzymatically removing the terminal sialic acids from tumor and immune cell surfaces. This approach solves for two of the main challenges in developing glyco-immunology therapeutics: the high degree of receptor redundancy and the vast number of distinct sialoglycan structures.
Our EAGLE platform is based on engineered human sialidase enzymes that degrade sialoglycans on tumors and across immune cell types. Engineering human sialidases for manufacturability and stability was a key element in the development of the EAGLE platform, as these enzymes have an inherently poor expression profile. Multiple EAGLE therapeutic candidates are under development in oncology, including Bi-Sialidase, several tumor-associated-antigen-targeted sialidases, and immune cell-targeted sialidases. View our pipeline >
Palleon has developed the powerful HYDRA platform to support our portfolio of cancer therapeutic candidates. HYDRA is an immunohistochemistry-based translational research technology which allows the identification of a patient’s specific tumor surface sialoglycan signature. Previously undetectable cell surface glycan patterns can now be interpreted by HYDRA.
We are leveraging HYDRA for indication prioritization, as well as for future clinical patient enrichment strategies and to guide optimal dosing of our therapeutic candidates.
Changes in sialylation can also contribute to immune dysfunction in inflammatory and autoimmune diseases. Research has shown a correlation between low levels of sialylation and autoimmunity. Targeting sialoglycans and/or their receptors could have therapeutic potential in suppressing the immune system in these diseases. Palleon is developing multiple strategies, including glycan-editing and Siglec-targeting programs, to address this therapeutic area.
Carolyn Bertozzi TedTalk – What the sugar coating on your cells is trying to tell you
Palleon co-founder Carolyn Bertozzi talks about how sugars on cancerous cells interact with (and sometimes trick) your immune system.
Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion
Published in 2013, Carolyn Bertozzi and colleagues demonstrate for the first time that increasing sialoglycans on cancer cells inhibits human natural killer (NK) cell activation through the recruitment of Siglec-7.
Interactions between Siglec-7,9 receptors and ligands influence NK cell-dependent tumor immunosurveillance
Stephan von Gunten and colleagues show that the alteration of sialoglycan patterns on cancer cells may affect tumor immunity by altering the interactions between Siglec-9 on NK cells and ligands found on tumor cell surfaces.
Precision glycocalyx editing as a strategy for cancer immunotherapy
Carolyn Bertozzi and Han Xiao developed a bacterial sialidase and anti-HER2 antibody conjugate that was shown to enhance tumor cell susceptibility to antibody-dependent cell-mediated cytotoxicity (ADCC) by selectively desialylating tumor cells, even those expressing only moderate levels of HER2.
Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells
Heinz Laubli and colleagues demonstrated that targeting the Siglec-sialoglycan axis on T cells can increase anti-tumor immunity, and that upregulation of Siglec-9 on T cells reduces survival rates in some NSCLC patients.
Sialic acid ligands of CD28 block co-stimulation of T cells
Published in 2021, Jim Paulson demonstrated that sialic acid on T cells can function as a ligand that blocks CD28-mediated co-stimulation of T cells. This suggests that the upregulation of sialoglycans on T cells may contribute to T cell exhaustion.
Siglec-9 regulates an effector memory CD8+ T-cell subset that congregates in the melanoma tumor environment
Stephan Von Gunten and colleagues showed that cytotoxic T cells in melanoma were functionally inhibited by the presence of Siglec-9 ligands (sialoglycans) or by Siglec-9 agonizing antibodies.
Siglecs as immune-cell checkpoints in disease
This review article authored by Jim Paulson and Shiteng Duan discusses the importance of the Siglec family in immune cell signaling and approaches to targeting the Siglecs for the treatment of cancer and autoimmune diseases.
Targeted glycan degradation potentiates the anticancer immune response in vivo
Carolyn Bertozzi and colleagues designed a bacterial sialidase and anti-HER2 antibody conjugate that strips sialoglycans from breast cancer cells. In a mouse model, they showed that desialylation enhanced immune cell infiltration and activation and prolonged the survival of the mice.
The tumor glyco-code as a novel immune checkpoint for immunotherapy
Rodriguez, Schetters and von Kooyk share their views on the role of tumor glycosylation in immune evasion and how targeting glycans may offer new therapeutic options.