D1.442 - Design and Preclinical Development of a Bispecific Antibody Targeting IL11 and TL1A

Fibrosis constitutes a major global healthcare burden and is a common pathological outcome of chronic inflammatory diseases, ultimately leading to irreversible organ dysfunction and increased mortality. Despite advances in disease management, effective antifibrotic therapies remain limited, highlighting a critical unmet clinical need. Both IL11 and TL1A have been well documented as key mediators linking chronic inflammation to fibrogenesis. IL11 is increasingly recognized as a central driver of fibroblast activation, extracellular matrix deposition, and epithelial dysfunction, while TL1A promotes aberrant immune activation and sustains inflammatory and fibrotic signaling. We therefore hypothesized that simultaneous blockade of IL11 and TL1A could provide superior therapeutic benefit. To this end, we developed a half-life-extended bispecific antibody (bsAb), HX15105, designed to co-target IL11 and TL1A.

The binding affinity and functional blocking activity of HX15105 against each target were assessed using a comprehensive set of in vitro assays. IL11 classical signaling and trans-signaling inhibition were evaluated using IL11–responsive reporter assays. TL1A binding and functional blockade were characterized using TF-1 cell apoptosis assays and DR3–NF-κB–Luc reporter assays. 

HX15105 demonstrated markedly enhanced potency against IL11 compared with the benchmark antibody 9MW3811, effectively inhibiting both IL11 classical signaling and hyper–IL11–mediated trans-signaling. For TL1A, HX15105 bound recombinant TL1A with sub-nanomolar affinity and exhibited robust functional blocking activity in both TF-1 apoptosis assays and DR3–NF-κB reporter assays, with efficacy comparable to its parental antibody TLA0238-45 and the clinical benchmark RVT-3101. In vivo efficacy of HX15105 is currently being evaluated in multiple preclinical animal models relevant to fibrotic and inflammatory diseases.

HX15105 is a bispecific antibody that simultaneously neutralizes IL11 and TL1A while preserving the functional potency of each parental binding arm. Its strong dual-target inhibitory activity in vitro supports its potential to more effectively suppress inflammation-driven fibrotic processes, offering a promising therapeutic strategy for the treatment of fibrotic and autoimmune diseases across multiple clinical settings.