D1.441 - A Bispecific Antibody Targeting IL13 and IL31 for the Treatment of Inflammatory Skin Diseases

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disorder characterized by persistent inflammation and severe pruritus. IL13 and IL31 are clinically validated therapeutic targets in AD, serving as key mediators of inflammatory responses and itch, respectively. To achieve enhanced therapeutic benefit, we developed a half-life-extended bispecific antibody (bsAb), HX16108, designed to simultaneously target IL13 and IL31.

The biological activities of HX16108 against each target were characterized using a panel of in vitro assays. Binding affinities were determined by surface plasmon resonance (SPR). Functional activity of the IL13–targeting arm was assessed using IL13 reporter assays and TF-1 cell proliferation assays, while the IL31–targeting arm was evaluated using I31 reporter assays and CCL2 secretion assays. The synergistic effect of dual cytokine blockade was examined by measuring IL-6 secretion in DU145 cells co-stimulated with IL13 and IL31. In vivo efficacy was evaluated in an IL13 + OVA–induced airway inflammation model in hTL1A transgenic mice and in an IL31–induced pruritus model in non-human primates.

HX16108 binds IL13 with sub-nanomolar affinity and effectively inhibits IL13–mediated downstream signaling and TF-1 cell proliferation, exhibiting potency comparable to benchmark Lebrikizumab analogue. Simultaneously, HX16108 demonstrates sub-nanomolar binding affinity to IL31 and blocking activity comparable to the benchmark antibody BMS-981164 in both IL31 receptor reporter assays and CCL2 secretion assays. Importantly, HX16108 showed a synergistic inhibitory effect on DU145 cell activation induced by combined IL13 and IL31 stimulation, exceeding the efficacy of either monospecific antibody alone. The bsAb also displayed IgG-like in vivo stability in rats. In the airway inflammation model, HX16108 significantly reduced pulmonary inflammation and decreased multiple immune cell populations in bronchoalveolar lavage fluid (BALF). In the non-human primate pruritus model, HX16108 markedly suppressed IL31–induced scratching behavior.

HX16108 simultaneously targets and blocks IL13 and IL31, effectively suppressing key inflammatory pathways and pruritic responses while exerting a synergistic therapeutic effect. It thus holds substantial potential for enhancing therapeutic outcomes in patients with atopic dermatitis and other inflammatory skin conditions.