Recent scientific advances have revealed that certain glycan (complex carbohydrate) patterns on cell surfaces are drivers of immune suppression in a high percentage of cancer patients and can also impact disease progression and therapeutic response in many autoimmune and inflammatory diseases. Scientific nuances inherent to glycobiology limit conventional approaches to drug discovery in this emerging field. Palleon has created a proprietary drug discovery platform that overcomes technical barriers and uniquely enables immune modulation by therapeutic degradation of pathologic cell surface glycans.
Our Approach
EAGLE Platform
Sialoglycans are a family of glycans found on cell surfaces that normally prevent the immune system from attacking healthy cells, but they can be co-opted as camouflage and prevent the immune-mediated clearance of pathogenic cells driving autoimmunity and cancer. Targeting sialoglycan biology offers great potential for developing new therapies for these diseases but is difficult to address with conventional drug development strategies. Whereas protein-protein interactions typically rely on one-to-one binding relationships that can be targeted and disrupted by a single blocking antibody or small molecule, sialoglycans and their receptors—like the clingy surface of Velcro—work through many touchpoints and therefore require a new approach.
Palleon’s EAGLE (Enzyme-Antibody GLycan Editing) Platform enables the targeted degradation of all immune suppressive sialoglycans on cell surfaces simultaneously by removing their terminal sialic acid molecules with sialidase enzymes, which makes pathogenic cells vulnerable to clearance by the immune system. The EAGLE platform can be applied to both autoimmunity and cancer.
A New Frontier in Biology
Palleon Scientific Co-Founder and Nobel laureate Carolyn Bertozzi’s discoveries in the field of glycobiology enabled the development of Palleon’s glycan editing therapeutic platform.
The Opportunity in Autoimmunity
Palleon’s lead candidate, E-602 employs a unique dual mechanism that enhances depletion of two distinct pathogenic immune cell subsets in autoimmunity—autoreactive memory B cells and pro-fibrotic macrophages—by enzymatically degrading sialoglycans on their cell surfaces.
Memory B cells are long-lived cells that enable immune memory by secreting antibodies to previously encountered antigens. Memory B cells can become dysfunctional in autoimmunity by producing autoantibodies which target the body’s own tissues. B cell depletion is a clinically validated strategy for treating autoimmune disease, and studies have shown that inadequate depletion of a critical B cell subset—CD27+ memory B cells—is a predictor of relapse. E-602 degrades sialoglycans on memory B cells, which are naturally hypersialylated, making them more susceptible to antibody-mediated depletion.
M2 macrophages play an important role in healthy wound healing and scar formation. CD163+ M2 macrophages are a subset of macrophages that can become dysfunctional in autoimmunity, causing excess collagen deposition, fibrosis, and loss of organ function. Macrophage reduction is a clinically validated strategy to treat autoimmune disease. High levels of sialoglycans allow dysfunctional CD163+ M2 macrophages to persist in inflamed tissue. Desialylation by E-602 reduces the prevalence of pro-fibrotic M2 macrophages, thereby reducing fibrosis in the patient with autoimmunity.
Creating a safe, effective and convenient solution for autoimmune disease in the outpatient setting
Recent success with CD19 CAR T therapy and T cell engagers has strengthened the hypothesis that deeper B cell depletion can achieve meaningful clinical results in autoimmunity, however, these approaches have severe toxicity risks including cytokine storm and neurotoxicity. E602 has a proven safety profile in humans and is expected to enhance depletion of the critical subset of B cells – autoreactive memory B cells – as well as impact tissue remodeling and fibrosis by reducing the prevalence of pro-fibrotic CD163+ M2 macrophages. This unique dual mechanism targeting two different pathogenic immune cell subsets can be achieved without the severe safety risks associated with emerging T cell therapies, making it suitable for the community outpatient setting.
Targeted Sialidase Molecules in Cancer
The majority of solid tumors are hypersialylated, especially lung cancer, ovarian cancer, and colon cancer, and preclinical and human translational evidence demonstrates that tumor surface hypersialylation is a major driver of immune suppression and resistance to therapy. Palleon is developing targeted sialidase molecules comprising a human sialidase enzyme and a tumor antigen targeting arm. These first-in-class tumor sialoglycan degraders enzymatically remove sialic acid, which disrupts the immunosuppressive barrier on hypersialylated tumors, making them more vulnerable to anti-tumor immunity.
HYDRA Platform
Palleon has developed the powerful HYDRA platform to support our portfolio of therapeutic candidates. HYDRA is an immunohistochemistry-based translational research technology that measures the density of hypersialylation on tissue samples. It provides a clinical biomarker and could potentially be used in the future as a companion diagnostic.