Targeting an IL-17/IL-36 pathogenic hub in hidradenitis suppurativa with a bispecific antibody

Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder with a high unmet need, particularly for treatment-resistant tunnels. Integrated multiomics analysis revealed that HS tunnels are spatially organized, self-amplifying inflammatory circuits driven by synergistic IL-17/IL-36γ activation of a unique keratinocyte subset, which activates neutrophils and inflammatory fibroblasts. This mechanistic insight coupled with spatial coenrichment of IL-17A and IL-36R provided the rationale for HB0043, a bispecific antibody that leverages IL-36R binding to locally dual-block both cytokines. HB0043 outperformed IL-17A/IL-17F bispecific and parental antibodies in vitro. In a proof-of-concept trial (NCT06895499) involving severe, tunnel-dominant Hurley Stage III HS patients, HB0043 induced promising clinical responses. At week 16, patients demonstrated an 82.13% mean percentage reduction from baseline in total abscess and inflammatory nodule count (AN), while 100% and 80% achieved HiSCR50 and HiSCR75, respectively, alongside ultrasound-confirmed tunnel regression and no major short-term safety signals. Longitudinal plasma proteomics showed suppressed inflammation and restored metabolic homeostasis. By tracking these dynamic systemic alterations alongside local structural changes, our multiomics approach bridges the gap between focal tissue lesions and global systemic disease activity. These findings establish dual blockade of IL-17A and IL-36R as a potential therapeutic strategy, offering a targeted strategy for recalcitrant disease that effectively improves the anatomical therapeutic barriers of advanced hidradenitis suppurativa, thereby demonstrating that cross-pathway bispecific antibodies can dismantle complex inflammatory circuits to achieve structural tissue healing where traditional monotherapies consistently fail.