一种采用新型CD3结合物的CD19/BCMA双靶向VHH格式T细胞衔接器,具有增强的效力和安全性特征

Recently, B cell depletion therapies targeting CD19 or BCMA, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies such as Blincyto and Tecvayli, have shown great potential in treating systemic lupus erythematosus (SLE) and other autoimmune diseases (AID). Targeting B cells and plasma blasts expressing CD19 is a key therapeutic strategy in autoimmune disease. However, in some patients, disease may also be anchored in long-lived plasma cells in the bone marrow expressing BCMA but not CD19.This means that the strategy of targeting CD19 alone has limitation in the therapy of B cell depletion. Here, we have developed CD19/BCMA dual-targeting T cell engager(FPE024) to achieve more extensive depletion of pathogenic B cells. All components of FPE024, including the CD3 nanobody, exhibit excellent cross-species binding activity between human and cynomolgus monkey. This enables us to simultaneously conduct safety and efficacy tests on cynomolgus monkeys, facilitating better translational studies bridging to clinical trials. FPE024 exhibits strong cytotoxicity in tumor cells with different CD19 and BCMA expression patterns, and the level of cytokine release is comparable to that of Blincyto and Tecvayli, indicating that FP024 has a good safety profile. FPE024 induces relatively similar B-cell killing in PBMC from healthy volunteers and SLE patients. In conclusion, FPE024 is a highly potent, CD19/BCMA dual-targeting TCE with preclinical data providing a strong rationale for broad development in AID which benefits from B cell depletion.