0908: E-602 (Efgitasialase alfa) Enhances Memory B Cell Depletion and Reduces Profibrotic Macrophages via Desialylation in Autoimmune Disease

Background/Purpose: Abnormal cell surface glycosylation has been observed in various autoimmune diseases, including systemic lupus erythematosus (SLE) and membranous nephropathy. Among these glycan modifications, sialoglycans function as immune-inhibitory molecules that pathogenic cells, such as cancer cells and pathogenic immune cells, exploit to evade immune surveillance. Elevated levels of surface sialoglycans have been detected on memory B cells and other pathogenic immune subsets in autoimmune conditions, contributing to their resistance to immune-mediated clearance and conventional therapies. Clinical studies have linked poor depletion of CD27⁺ memory B cells to suboptimal treatment outcomes. This study investigates E-602, an engineered human sialidase, as a novel therapeutic approach to enzymatically remove sialoglycans from the surface of pathogenic immune cells.

Methods: We assessed the effect of E-602-mediated desialylation in ADCP and CDC assays using Raji cells or human primary B cells from healthy donor PBMCs in the presence of anti-CD20 or anti-CD19 antibodies. We then evaluated its impact on depleting CD27+ memory B cells using PBMCs from SLE patients. In vivo efficacy was tested in a lymphoma mouse model, an MRL/lpr SLE mouse model, and non-human primates. We also investigated whether E-602 reduces profibrotic M2-like macrophages in chronically inflamed tissues using tumors as a surrogate in mouse tumor models.

Results: E-602 enhanced ADCP and CDC across multiple anti-CD20 and anti-CD19 B cell-targeting antibodies. It improved anti-CD20-mediated depletion of CD27+ memory B cells by ~50% from SLE patients, which express high levels of sialoglycans and are typically resistant to depletion using anti-CD20 antibodies alone. In lymphoma and MRL/lpr SLE mouse models, E-602 enhanced anti-CD20-mediated B cell depletion. In non-human primates, E-602 improved B-cell depletion in lymph nodes, which are often resistant to B-cell depletion compared to peripheral blood. Additionally, E-602 reduced profibrotic M2-like macrophages by ~ 90% compared to the vehicle control in the tumor microenvironment, which serves as a surrogate for chronic inflammatory tissue.

Conclusion: E-602 offers a novel therapeutic strategy through enzymatic desialylation of pathogenic immune cells to enhance their depletion and restore immune balance. Its dual MoA targets two key pathogenic subpopulations: memory B cells, which drive autoantibody production and contribute to disease relapses, and M2-like macrophages, which promote fibrosis and organ damage. This combination could potentially improve tissue level B cell depletion and reduce pro-fibrotic macrophage induced tissue damage. Based on a favorable safety and tolerability profile demonstrated in the completed Phase 1 GLIMMER-01 trial in oncology patients, E-602 represents a scientifically novel, safe, and broadly applicable add-on to existing B-cell-targeting antibody therapies in a wide range of patients with autoimmune diseases.