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B cells contribute to multiple aspects of autoimmune disorders through autoantibody production, antigen presentation, cytokine secretion, and formation of tertiary lymphoid structures. B cell targeting therapies have been developed and approved for treatment of autoimmune diseases. Many approved B cell targeted therapies deplete B cells through targeting CD20 (rituximab, ocrelizumab, etc). However, CD20-mediated B cell depletion has limitations including incomplete depletion of tissue resident pathogenic B cells, inability to target CD20-negative B cells (plasmablasts), and a long recovery time for B cells. Thus, developing therapies with more efficacy on tissue resident B cells and a non-depleting mechanism of action is highly desirable. Here we describe a novel, non-depleting, B cell inhibiting, anti-human CD19 antibody LY3541860 which binds human and cynomolgus monkey (cyno) CD19 with high affinity, does not induce ADCC or CDC, and does not cause B cell apoptosis. LY3541860 inhibited B cell activation, proliferation, and differentiation of primary human and cyno B cells ex vivo. LY3541860 also inhibited human B cell activation in vivo in humanized mice. Administration of anti-CD19 antibodies in cyno did not cause reduction of B cells and resulted in complete receptor occupancy. We also developed a non-depleting anti-mouse CD19 antibody with similar characteristics as the anti-human CD19 antibody. The anti-mouse CD19 antibody was used to compare effects of B cell inhibition with B cell depletion in multiple mouse models of autoimmunity. Our data demonstrate that treatment with the anti-mouse CD19 antibody ameliorated clinical symptoms in multiple mouse autoimmune models including collagen-induced arthritis (CIA), non-obese diabetic (NOD) and experimental autoimmune encephalomyelitis (EAE). Moreover, this anti-mouse CD19 antibody demonstrated improved efficacy in all tested mouse autoimmune models compared with an anti-CD20 depleting antibody. No B cell depletion was noted in any of the in vivo models tested while B cell depletion was evident with the anti-CD20 antibody. Improved efficacy seen with the non-depleting CD19 antibody may be due to targeting CD20-/CD19+ plasmablasts, as well as bypassing limited B cell depletion in tissues. Taken together, these data suggest that a non-depleting anti-CD19 antibody may demonstrate superior efficacy in treatment of autoimmune conditions compared with B cell depleting therapies.