Background/Purpose: IL-23 is a pivotal cytokine driving IL-17-mediated inflammation, and its inhibition has shown efficacy in Th17-associated autoimmune diseases. However, patient heterogeneity and compensatory pathways limit therapeutic responses. The IL-36/IL-36R pathway contributes to inflammation and barrier homeostasis, with its hyperactivity related to multiple autoimmune diseases and implicated in resistance to IL-23/IL-17 inhibitors in psoriasis. Here we developed an anti-IL-23/IL-36R bispecific antibody (BsAb) to block both pathways, aiming to improve clinical outcomes across autoimmune indications.

Methods: The synergistic effect of the two pathways was validated in an intradermal dual-cytokine (IL-23 plus IL-36)-challenging murine model. The binding to targets was evaluated by Surface Plasmon Resonance (SPR) and Fluorescence-Activated Cell Sorting (FACS). The blockade of IL-23 and IL-36 signaling was separately assessed by Ba-F3 cell proliferation assay and the assay of IL-8 secretion in A431 cells. The simultaneous blockade of both pathways was assessed in a PBMC/A431 co-culturing system. In vivo efficacy of BsAb was evaluated in an IL-23/IL-36 co-induced murine psoriasis model. The safety profile was evaluated in a 4-week repeated-dose Good Laboratory Practice (GLP) toxicology study in cynomolgus monkeys.

Results: Intradermal dual-cytokine challenge induced exacerbated psoriasiform pathology in mice, including epidermal hyperplasia and upregulated pro-inflammatory cytokines, suggesting the synergistic effect between IL-23 and IL-36 pathways. The anti-IL-23/IL-36R BsAb demonstrated high-affinity binding to both IL-23 and IL-36R, and inhibited IL-23-dependent Ba-F3 proliferation and IL-36R-mediated inflammatory responses, with activities comparable to those of the corresponding monospecific antibodies. In the PBMC/A431 co-culture assay, the BsAb surpassed monospecific antibodies in suppressing psoriasis-related cytokines. In a murine psoriasis model induced by IL-23/IL-36 co-stimulation, the BsAb outperformed monospecific antibodies in reducing ear thickness and suppressing multiple pro-inflammatory cytokines and keratinocyte hyperproliferation markers. Non-human primate studies revealed no drug-related toxicity at all tested doses.

Conclusion: Our data highlight the enhanced therapeutic efficacy of the anti-IL-23/IL-36R BsAb through concurrent inhibition of two complementary signaling pathways, without compromising safety profile. This dual-targeting therapeutic shows promise for treating diverse autoimmune diseases, including psoriasis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preclinical-characterization-of-a-novel-bi-specific-antibody-targeting-il-23p19-and-il-36r-for-the-treatment-of-autoimmune-diseases/