Beyond monospecificity in systemic lupus erythematosus: Emerging roles of bispecific and trispecific antibodies

Purpose Targeted biologic therapy has changed the management of systemic lupus erythematosus (SLE), including lupus nephritis (LN), but incomplete response, relapse, glucocorticoid dependence, and refractory organ disease remain common. This article discusses whether bispecific and trispecific antibodies may help move lupus therapy beyond conventional monospecific blockade. Key Messages Multispecific antibodies are not a single therapeutic class. Their clinical relevance depends on mechanism: dual-pathway blockade, interruption of B-T-cell collaboration, inhibitory non-depleting B-cell silencing, T-cell engager-mediated depletion of B-cell or plasma-cell compartments, and future trispecific immune-reprogramming concepts. Direct lupus evidence remains limited. Obexelimab, which co-engages CD19 and the inhibitory receptor FcγRIIb, provides the most informative randomised SLE dataset, but its phase 2 trial did not meet the primary endpoint and biomarker-defined signals remain hypothesis-generating. Teclistamab, a BCMA × CD3 T-cell engager, offers a provocative single-case proof of concept in refractory SLE with active LN, but also illustrates risks of cytokine release syndrome, infections, and hypogammaglobulinaemia. Rozibafusp alfa, which targets ICOSL and BAFF, illustrates the biological appeal, and clinical difficulty, of rational dual-pathway blockade in SLE. Conclusions Multispecific antibodies may become useful in lupus if their depth of immune intervention can be matched to disease phenotype, safety risk, and trial design. Their future role will depend on lupus-specific evidence, biomarker-guided selection, and careful positioning between conventional biologics and cellular immune-reprogramming strategies.