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Background The IL-18/IL-18BP axis represents a promising immunotherapeutic target in oncology.IL-18, a potent cytokine in the tumor microenvironment (TME), enhances antitumor immunity by activating antigen-experienced tumor-infiltrating lymphocytes, expanding T cell repertoire diversity, and activating NK cells and monocytes, thereby amplifying immune cell-mediated tumor killing.However, IL-18 binding protein (IL-18BP), a high-affinity soluble decoy receptor, sequesters IL-18 and limits its anti-tumor activity.IL-18BP is overexpressed in various tumors, with expression levels negatively correlating with patient survival and positively correlating with checkpoint inhibitor resistance.Previous clinical failures of recombinant IL-18 therapy are attributed to IL-18BP neutralization, highlighting the therapeutic potential of IL-18BP blockade.Given high IL-18BP expression levels and regulation, current IL-18BP blockers face potential saturation challenges that reduce effectiveness.To address this, we developed pH-sensitive IL-18BP binders that function through IL-18 release and enhanced IL-18BP degradation, resulting in longer-lasting antibody activity.Methods We developed a high-affinity antibody targeting IL-18BP.In vitro studies evaluated its ability to block IL-18BPmediated IL-18 sequestration and restore IL-18 bioactivity.In vivo tumor xenograft models assessed anti-tumor efficacy, tumor penetration, immune cell activation, and cytokine production.Comparative studies with existing anti-IL-18BP approaches evaluated best-in-class potential.Results Our antibody exhibited pH-sensitive binding to IL-18BP and effectively blocked IL-18 sequestration at neutral pH, resulting in enhanced free IL-18 availability.In preclinical tumor models, treatment significantly improved and activated IL-18-mediated T cell and NK cell responses.The antibody activated both innate and adaptive anti-tumor immunity while avoiding systemic immune activation.It demonstrated best-inclass in vivo efficacy and synergy with checkpoint inhibitors.Conclusions Our anti-IL-18BP antibody represents a promising best-in-class therapeutic candidate with superior preclinical efficacy.By targeting the IL-18/IL-18BP axis, it restores IL-18mediated anti-tumor immunity through local TME activation while maintaining improved tolerability compared to systemic IL-18 or IL-18 mutein administration.The combination of improved tumor penetration and pH-sensitive binding demonstrates superior efficacy, further validating the anti-IL-18BP therapeutic class following recent entries into first-in-human studies.