POS0998 CC312, A CD19-TARGETING, CO-STIMULATORY CD28 RECEPTOR-ACTIVATING TRI-SPECIFIC T CELL ENGAGER, FOR THE TREATMENT OF AUTOIMMUNE DISEASES

作者：Ying Huang, Xian Zhang, Chunling Zhao, R Zhang, Juan Zhen, Feng Pan, Bo Zheng, Rongyang Dai · 发表于：Annals of the Rheumatic Diseases · 年份：2025 · DOI：10.1016/j.ard.2025.06.353 · 被引用次数：2 · 研究领域：Cancer Immunotherapy and Biomarkers、T-cell and B-cell Immunology、Immunodeficiency and Autoimmune Disorders

Background: B cell depletion therapy (BCDT), such as monoclonal antibodies, bispecific T cell engagers and CAR-T, has an extensive history of effectively treating B cell malignancies. Certain BCDT monoclonal antibodies, e.g. rituximab, are also approved to treat several autoimmune diseases [1], however demonstrate poor B cells depletion in deep tissue which may limit the long-term disease control or remission in patients. Recently, anti-CD19 CAR-T therapies, through thorough depletion of pathogenic B cells and "resetting" of normal B cell populations, have achieved compelling preliminary clinical efficacy including multi-year drug-free remission in multiple autoimmune diseases [2, 3], however CAR-T modality continues to pose challenges regarding safety, cost, and logistical complexity. T Cell Engagers (TCEs) represent an attractive alternate option to CAR-T, with approved CD19-targeting bispecific TCE Blincyto demonstrating strong potential in RA [4]. However, existing bispecifics have displayed key limitations such as T cell exhaustion, poor T cell proliferation, and insufficient durability of response. Here, we developed the tri-specific TCE CC312, targeting CD3 and the key co-stimulatory receptor CD28 on T cells and CD19 on B cells. By adding critical CD28 "two signal" co-stimulation, CC312 showed efficacy consistent with CAR-T therapies, achieving greater CD4/CD8 T cell activation, proliferation, T cell survival and B cell depletion versus Blincyto in a prior study in B c...