Immune cell engagers (ICEs) offer a promising approach for achieving deep depletion of pathogenic B cell populations in systemic autoimmune diseases. Their modular design enables the recruitment of T cells, natural killer cells, γδ T cells or myeloid cells to eliminate B cells, plasmablasts and long-lived plasma cells. Use of ICEs in haematological malignancies has established the therapeutic potential of targeting the lineage antigens of B cells and plasma cells, and informed understanding of resistance, treatment-associated toxicity and incomplete target-cell depletion. However, applications in autoimmune diseases present distinct challenges, including disease-specific B cell heterogeneity, pharmacokinetic limitations, effector-cell dysfunction and the risk of cytokine release syndrome. Despite these challenges, early clinical reports using CD19-directed and B cell maturation antigen-directed T cell engagers have shown sustained improvements in several systemic autoimmune diseases. In this Review, we discuss the principles guiding ICE development for autoimmune diseases, including target selection, engager architecture, effector-cell recruitment and safety. We also consider emerging strategies, including CD8-biased T cell engagement, co-stimulatory multispecific formats, and natural killer or γδ T cell recruitment, to improve safety and durability of response. ICEs could ultimately provide an off-the-shelf alternative to chimeric antigen receptor T cell therapies, enabling sustained immune reprogramming in patients with refractory autoimmune diseases.
