Background/Purpose: CD180 is a Toll-like receptor (TLR) homolog expressed on antigen-presenting cells (APCs): B cells, dendritic cells, monocytes, and macrophages. While the extracellular domain of CD180 is structurally similar to other TLRs, intracellular signaling is distinct from classical TLRs as CD180 lacks a TIR domain. Instead, CD180 signaling leads to pleiotropic downstream immune responses, including PI3K activation and downregulation of type I interferon (IFN)-associated inflammation. In mice, treatment with an agonistic anti-CD180 antibody is therapeutic in multiple models of lupus.

Methods: We utilize RNA-sequencing and transcriptional analysis of human B cells stimulated with humanized anti-CD180 monoclonal antibody to characterize CD180 signaling and predict diseases that may show therapeutic effect with anti-CD180 treatment. Mouse models of rheumatic disease are used to support these disease predictions.

Results: To support clinical development of anti-CD180 therapy, we have humanized G28-8, a mouse anti-human CD180 monoclonal antibody. Humanized G28-8 (hzG28-8), including the lead drug candidate ABB071, have retained primate CD180 cross-reactivity and functional profiles of the parent G28-8. RNAseq analysis revealed an inverse correlation between genes regulated by ABB071 in B cells from normal donors to genes differentially expressed in B cells from patients with rheumatic disease. Several genes upregulated in B cells from lupus patients, e.g., TLR7 and IRF5, were downregulated in ABB071 treated B cells. In contrast, genes downregulated in B cells from lupus patients, e.g., PNPT1 and DNASE1L3, were induced by ABB071. These results suggest a genetic connection between CD180 biology and the pathogenesis of autoimmune and inflammatory disorders.Suppression of IFN-stimulated genes (ISGs) was used to evaluate the therapeutic potential of ABB071. ABB071 inhibited ISGs induced by ligands for TLR7, TLR8, TLR9, cGAS-STING, as well as IFNα in B cells from normal donors. The effects of ABB071 against TLR7/8 ligand and IFNα was also observed in B cells from SLE patients. In addition, ABB071 down-modulated baseline expression of several genes in the type I IFN pathway including IFNAR1/2, IRF5, and IL-15. A mouse model of imiquimod-induced psoriasis was used to validate the role of CD180 signaling in suppressing inflammatory disease. Mice treated with anti-CD180 had reduced overall PASI scoring (psoriasis severity scoring), as well as reduced levels of key inflammatory cytokines in the skin. The safety margin of CD180 targeting in mice was confirmed by the finding that anti-CD180, up to 50 mg/kg, did not result in observable clinical side effects or increase in circulating proinflammatory cytokines such as IL-6, TNFα, and IFNɣ.

Conclusion: In contrast to most current approved therapies designed to neutralize individual cytokines or their receptors globally in patients, targeting CD180 is a novel strategy focusing the therapeutic actions on one of the most relevant subsets of immune cells, the APCs, to simultaneously suppress multiple key pro-inflammatory pathways. This study provides the rationale for clinical development of ABB071 in the treatment of autoimmune and inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preclinical-characterization-of-abb071-a-humanized-anti-cd180-antibody-that-modulates-multiple-pro-inflammatory-immune-pathways-for-the-treatment-of-autoimmune-and-inflammatory-disorders/