Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by immune system disorders related to the abnormal activation of B lymphocytes, massive production of autoantibodies, and deposition of immune complexes. B-Cell Maturation Antigen (BCMA), a member of the tumor necrosis factor receptor superfamily, is specifically expressed on the surface of plasma cells. It is a key molecule regulating the survival, differentiation of plasma cells and the secretion of autoantibodies, and is abnormally highly expressed in the peripheral blood and affected tissues of SLE patients, making it an important target for targeted intervention in SLE. Teclistamab is a humanized bispecific antibody targeting BCMA on target cells and CD3 on T cells. As a T Cell Engager (TCE), it binds to BCMA antigens on the surface of tumor/abnormal immune cells at one end and to the CD3ε chain on the surface of T cells at the other end, thereby forcibly bringing T cells closer to target cells, activating T cells, and enabling the directional killing of target cells. Previously, we successfully established a spontaneous SLE model in transgenic mice with overexpression of human BAFF. In order to better evaluate the efficacy of CD3/BCMA-related drugs candidates, we crossed this mouse strain with CD3/BCMA humanized mice to obtain BAFF/CD3/BCMA dual-target humanized mice and performed drug efficacy study in this model.

Objectives: To establish a scientific and comprehensive preclinical efficacy evaluation system for CD3/BCMA TCE antibodies using SLE mouse models, facilitating the clinical translation of such drugs.

Methods: Serum of wild-type and hBAFF/hCD3/hBCMA mice aged 12 to 28 weeks old was collected, and anti-dsDNA autoantibody, IgG and IgM levels were detected using an ELISA kit. Flow cytometer was used to detect the proportion and number of hBCMA ⁺ plasma cells in the peripheral blood. In addition, we conducted the pharmacodynamic experiment of Teclistamab using 12-week-old hBAFF/hCD3/hBCMA mice by injecting Teclistamab intraperitoneally twice a week for 16 weeks. During the administration period, serum was collected to detect anti-dsDNA autoantibody, IgG and IgM levels. Peripheral blood was collected to detect the proportion and number of hBCMA ⁺ plasma cells by flow cytometry.

Results: We observed similar spontaneous SLE phenotype in the hBAFF/hCD3/hBCMA mice as seen in the B6-hBAFF mice, including a significant increase in the IgG and IgM levels in serum at 12 weeks of age compared with wild-type mice, which continued to increase gradually as the transgenic mice aged. These mice secreted a high level of anti-dsDNA autoantibodies, along with an increased ratio of plasma cells/CD45 in the blood compared with wild-type mice, indicating overreactive B cells. Two weeks after Teclistamab treatment, the levels of IgG, IgM and anti-dsDNA autoantibodies in the serum were significantly reduced. Additionally, the numbers and proportions of plasma B cells and hBCMA+ plasma cells in the peripheral blood significantly decreased two weeks post treatment, indicating that Teclistamab alleviates the SLE phenotype.

Conclusions: We have developed a novel spontaneous SLE model for evaluating CD3/BCMA-related antibody based on the hBAFF/hCD3/hBCMA mice for efficiency evaluation in autoimmune disease.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.