Beyond monospecificity in systemic lupus erythematosus: Emerging roles of bispecific and trispecific antibodies
- 1Department of Medical Sciences, University of Turin, Turin, Italy
- 2Immunology and Allergy Unit, AO Ordine Mauriziano di Torino, Turin, Italy
Abstract
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.
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BibTeX
@article{negrini2026beyond,
title = {{Beyond monospecificity in systemic lupus erythematosus: Emerging roles of bispecific and trispecific antibodies}},
author = {Simone Negrini and Stefania Nicola and Luisa Brussino},
journal = {Lupus},
year = {2026},
month = oct,
doi = {10.1177/09612033261493822},
url = {https://doi.org/10.1177/09612033261493822},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Beyond monospecificity in systemic lupus erythematosus: Emerging roles of bispecific and trispecific antibodies
AU - Simone Negrini
AU - Stefania Nicola
AU - Luisa Brussino
PY - 2026
DA - 2026/10/07
JO - Lupus
DO - 10.1177/09612033261493822
UR - https://doi.org/10.1177/09612033261493822
AB - 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.
SN - 0961-2033
SN - 1477-0962
ER -