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bioRxiv · 10.1101/2025.09.16.676329

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

Biris, N.·Zhao, C.·Macoin, J.·Fuller, J. R.·Blauvelt, A.·Chovatiya, R.·Bunick, C. G.
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Abstract

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

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Biris, N., Zhao, C., Macoin, J., Fuller, J. R., Blauvelt, A., Chovatiya, R., Bunick, C. G.. 2025-09-19. A Dual-Action Mechanism to Prevent OX40 Signaling: The Structural Basis for the Differentiated Antagonist STAR-0310. https://doi.org/10.1101/2025.09.16.676329

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