Background/Purpose: B-cell-activating factor (BAFF) plays a critical role in B cell survival, and its elevated expression can contribute to the presence of autoreactive B cells, potentially leading to autoimmune conditions like Systemic Lupus Erythematosus (SLE). To deepen our understanding of these mechanisms, GemPharmatech developed a transgenic mouse model featuring human BAFF overexpression. This model offers insights into SLE pathogenesis and serves as a relevant preclinical tool for assessing therapies targeting B cells.

Methods: We constructed a human BAFF coding vector and introduced it into B6 mouse embryos. Positive mice were selected and subjected to phenotype validation for SLE. Sera were collected for immunoglobulin (Ig) analysis, and kidneys underwent histopathological examination and immune complex deposition analysis. SLE phenotype mice were treated with Bayeuzumab (a BAFF antibody) and Obutinib (a BTK inhibitor), and disease-related parameters were assessed post-treatment.

Results: In B6-hBAFF mice with human BAFF overexpression, significant increases in immunoglobulins (Igs) and anti-dsDNA levels were observed from 6 weeks of age, persisting over time compared to wild-type mice. These mice exhibited an expanded population of B cells, particularly marginal zone B cells, but a reduced T cell ratio. By 25 weeks of age, B6-hBAFF mice developed lupus nephritis, characterized by crescent formation, peripheral renal tubular atrophy, and intense C3 deposition.

Treatment with the anti-BAFF therapeutic antibody Belimumab effectively reduced serum IgA, IgM, IgG, and anti-dsDNA levels after 16 weeks of dosing. Belimumab also improved kidney function, as evidenced by reductions in urine albumin-to-creatinine ratio, lupus nephritis activity index, and IgA deposition in the kidney after 20 weeks of treatment. Notably, Belimumab led to reductions in plasma B cells, memory B cells, and T follicular helper cells in the spleen and blood compared to untreated mice. The BTK inhibitor Orelabrutinib also significantly lowered serum IgG, IgM, IgA, and anti-dsDNA levels, along with reductions in T follicular helper cell populations in blood, spleen, and lymph nodes, as well as decreased plasma cell populations in the spleen and lymph nodes.

Conclusion: The humanized BAFF transgenic mouse model exhibited an SLE-like phenotype similar to that observed in clinical patients, with disease pathogenesis linked to B cell overactivation. This model demonstrated a comparable efficacy response to clinical drug treatments targeting B cells. Thus, it serves as a valuable tool for the development and evaluation of therapeutic drugs for SLE related to B cell therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluating-the-efficacyof-b-cell-targeting-drug-candidates-using-a-humanized-baff-transgenic-sle-mouse-model/