Dual Inhibition of TNF-α and IL-6R mitigates cytokine release syndrome via protection of endothelial integrity and reduction of organ damage in mouse models.

Authors

Hyeyun Won, Eunyoung Park, Yun-Gil Roh, Mincheol Kang, Nari Kim

Published in

Frontiers in immunology. Volume 17. Pages 1848290. Epub Jul 10, 2026.

Abstract

Cytokine Release Syndrome (CRS) is a life-threatening complication of T-cell-engaging immunotherapies, causing vascular leakage and multi-organ dysfunction. Standard Interleukin-6 (IL-6) blockade often fails in severe cases by leaving the upstream initiator, Tumor Necrosis Factor-α (TNF-α), unchecked. TNF-α drives early macrophage activation and endothelial injury, whereas IL-6 amplifies systemic inflammation. To decisively interrupt this inflammatory feedback loop, we developed IDC007, a novel bispecific antibody simultaneously neutralizing TNF-α and IL-6 receptor (IL-6R).
We evaluated the neutralizing effects of IDC007 in an in vitro CRS model utilizing OKT3/R848-stimulated human peripheral blood mononuclear cells and human umbilical vein endothelial cells. Furthermore, we utilized an OKT3-induced humanized CRS mouse model to assess in vivo target engagement and therapeutic efficacy.
In vitro, IDC007 effectively suppressed pro-inflammatory cytokine secretion (e.g., TNF-α, IFN-γ) and prevented endothelial barrier dysfunction. In vivo, IDC007 successfully engaged both targets. Administration mitigated physiological deterioration, including hypothermia and weight loss, leading to improved survival. Dual inhibition effectively prevented immune hyperactivation, evidenced by the significant attenuation of splenomegaly and lung-specific organ damage.
These findings serve as a preclinical proof-of-concept demonstrating that dual targeting of TNF-α and IL-6R offers a potent mechanistic approach to attenuate severe CRS by preserving vascular endothelial integrity and overcoming the therapeutic limitations of conventional monotherapies.

PMID:
42500657
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.

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