A Dual-Action Mechanism to Prevent OX40 Signaling: The Structural Basis for the Differentiated Antagonist STAR-0310

Atopic dermatitis (AD) is a chronic inflammatory disease sustained by dysregulated T cell activity. The OX40/OX40L pathway drives effector and memory T cell proliferation, survival, and cytokine production, making it a key therapeutic target. STAR-0310, a novel anti-OX40 antibody, binds a noncanonical epitope that sterically blocks receptor trimerization without inducing agonism. Structural and functional studies demonstrated a dual mechanism: prevention of new OX40/OX40L interactions and efficient disruption of pre-formed complexes, outperforming comparator antibodies. The pure antagonism and complex disruption capacity of STAR-0310 support its clinical evaluation (NCT06782477) as a differentiated OX40-targeted therapy for AD. HighlightsO_LINovel binding mechanism: STAR-0310 engages OX40 distal to the OX40L site, sterically blocking receptor trimerization without inducing agonism. C_LIO_LIDual action: Prevents formation of new OX40/OX40L complexes and efficiently disrupts pre-formed complexes sustaining inflammation. C_LIO_LIDifferentiation from competitors: Achieves greater efficiency in complex disruption compared with rocatinlimab and IMG-007 with no partial agonist activity. C_LIO_LIClinical potential: Pure antagonist profile supports ongoing evaluation of STAR-0310 (NCT06782477) as a best-in-class OX40 therapy for atopic dermatitis. C_LI