Background/Purpose: CD20, a well characterized B-cell surface marker involved in B-cell activation and differentiation, plays a critical role in the pathogenesis of B-cell mediated diseases such as B-cell lymphomas, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Due to its selective expression on B-cells, CD20 is an attractive target for antibody therapies targeting B-cell related diseases. Previously, we established a SLE model in transgenic mouse strains through the overexpression of human BAFF on a C57BL/6 mouse background (B6-hBAFF,T036794). To facilitate the preclinical evaluation of CD20-targeted therapeutics, we further developed a dual humanized model by crossing this mouse strain with CD20 humanized mice (BALB/c-hCD20,T057498) to obtain BAFF/CD20 dual-target humanized mice(T065937).

Methods: Serum samples from wild-type mice, hBAFF mice and hBAFF/hCD20 mice aged 8 to 27 weeks old were analyzed for anti-dsDNA autoantibodies, total IgG and IgM level via ELISA. Spleens and peripheral blood were also collected to assess B-cell populations by flow cytometry. To evaluate pharmacological response, 8-week-old hBAFF/hCD20 mice received intraperitoneal injections of ritixumab twice weekly for 20 weeks. During the administration period, serum and blood samples were collected for longitudinal assessment of immunoglobulin levels and B-cell counts.

Results: The hBAFF/hCD20 mice demonstrated a spontaneous SLE-like phenotype comparable to B6-hBAFF mice. These included elevated levels of serum IgG and IgM levels beginning at 8 weeks of age, which increased progressively as animals aged. High levels of anti-dsDNA autoantibodies, along with an increased ratio of B-cell frequency in the spleen and blood were observed, confirming an autoimmune phenotype. Following 60 days of rituximab treatment , the levels of IgM and anti-dsDNA antibodies in the serum were reduced, while the level of IgG was unchanged. By day 79, the numbers and proportions of total CD19+ B cells and plasma B cells in the peripheral blood significantly decreased, suggesting effective B-cell depletion and attenuation of the SLE phenotype.

Conclusion: We have established a novel dual humanized hBAFF/CD20 transgenic mouse model that exhibits spontaneous SLE features and enables the evaluation of CD20-targeted therapies. This model represents a powerful in vivo platform for investigating B-cell depleting agents in autoimmune disease settings.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-preclinical-tool-for-evaluating-cd20-antibody-efficacy-based-on-baff-cd20-dual-target-humanized-mice/