Establishment of a Systemic Lupus Erythematosus Mouse Model in Humanized CD3/CD19 Mice and Evaluation of the Efficacy of a Human Bispecific Antibody

Abstract

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease affecting multiple organ systems and is considered one of the most severe autoimmune diseases worldwide, significantly impacting womens health. B cells play a crucial role in disease pathogenesis by becoming abnormally activated and producing autoantibodies that attack the bodys normal tissues, leading to inflammation and organ damage. Therefore, targeting the human B cell receptor has emerged as a promising strategy for therapeutic intervention. In this study, we established an SLE animal model using double-humanized CD3/CD19 mice, in which human CD3 and CD19 genes replaced their murine counterparts. The phenotype was confirmed by ELISA and flow cytometry. hCD3/hCD19 mice induced by a combination of pristine x 2, imiquimod (IMQ) and nephrectomy exhibited several key features of SLE, including anti-dsDNA antibody production, proteinuria, increased immune cell populations, and kidney lesions. Furthermore, treatment of these humanized mice with anti-human CD3/CD19 bispecific antibodies significantly inhibited these pathological indicators. Thus, pristine x 2, IMQ and nephrectomy induced hCD3/hCD19 mice provide a validated preclinical model for investigating novel therapeutic agents targeting B cells in SLE. Graphical abstractThis study explores the effects of different modeling strategies on agent induction, with a particular emphasis on the link between the induced agents and their corresponding clinical manifestations. Through an extensive literature review and experimental validation, a novel approach for inducing systemic lupus erythematosus (SLE) has been established. By employing gene editing techniques, mouse CD3 and CD19 antibody recognition sites were substituted with their human equivalents. This humanized mouse model enables the direct assessment of humanized bispecific antibodies in the context of SLE induction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/668572v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@652c83org.highwire.dtl.DTLVardef@4d6233org.highwire.dtl.DTLVardef@6a2f8forg.highwire.dtl.DTLVardef@1587652_HPS_FORMAT_FIGEXP M_FIG C_FIG