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bioRxiv · 10.64898/2026.01.27.701893

An Advanced Humanized Systemic Lupus Erythematosus Model Enables Parallel Profiling of B Cell-Targeted Therapies

Zhu, R.·Ding, S.·Ren, D.·Liang, J.·Liu, S.·Fan, J.·Yu, S.·Zhang, Z.·Cheng, C.·Wang, K.·Chen, Y.·Hang, Y.·Shang, X.·Li, Y.·Sun, L.
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Abstract

B cell-targeted therapies represent a transformative frontier for systemic lupus erythematosus (SLE) intervention, yet clinical recommendation of specific treatment is hampered by the challenge to perform head-to-head comparisons of efficacy-toxicity trade-offs and tissue-specific impacts in patients. To address this gap, an advanced Toll-like receptor 7 (TLR7) agonist-induced SLE model is developed in a NCG-M (NOD-Prkdcem26Cd52Il2rgem26Cd22Rosa26em1Cin(hCSF2&IL3&KITLG)/Gpt) human immune system (HIS) mice. This model enables parallel evaluation of multiple B cell-directed therapies within a controlled cohort study. It recapitulates core SLE pathologies--including immune effector cell augmentation, autoantibody production and glomerulonephritis--within 2 months, demonstrating greater severity and clinical fidelity than conventional pristane-induced systems. Validated through replication of clinical responses to rituximab and belimumab, the platform directly compares two emerging modalities: universal chimeric antigen receptor-T cells (UCAR-T) elicits delayed but profound B-cell reset correlating with superior reduction in renal pathology and autoantibodies, while T cell engagers (TCEs) mediate rapid yet partial B-cell depletion and transient efficacy. UCAR-T concurrently induces greater acute inflammatory responses, aligning with its distinct toxicity profile. By resolving therapy-specific effects on human immune dynamics and symptom control, this study empowers context-specific therapeutic selection for SLE, advancing tailored management strategies.

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Zhu, R., Ding, S., Ren, D., Liang, J., Liu, S., Fan, J., Yu, S., Zhang, Z., Cheng, C., Wang, K., Chen, Y., Hang, Y., Shang, X., Li, Y., Sun, L.. 2026-01-29. An Advanced Humanized Systemic Lupus Erythematosus Model Enables Parallel Profiling of B Cell-Targeted Therapies. https://doi.org/10.64898/2026.01.27.701893

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