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Molecular differentiation of OX40- and OX40L-targeted biologics using AlphaFold3 and molecular dynamics simulations
Kelsey Nolden1, Yuanjun Shi2, Victor S Batista2
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Abstract:
Atopic dermatitis is a chronic inflammatory skin disorder that affects over 200 million people worldwide. Although disease etiology is multifaceted, the immune checkpoint molecules OX40 and OX40L have a critical role in disease development. Recent clinical trials demonstrated that the OX40-targeting antibodies rocatinlimab (KHK4083/AMG-451) and telazorlimab (GBR-830/ISB-830) and the OX40L-targeting antibody amlitelimab (KY1005) significantly improve symptoms of atopic dermatitis. However, the epitopes where these antibodies bind OX40 and OX40L remain unclear, and therefore, so do the mechanisms through which they specifically disrupt OX40-OX40L signaling. To address this, computational modeling was performed to predict antibody-protein cocomplexes, and their interaction interfaces were characterized. Binding-free energy of specific OX40 or OX40L residue-residue interactions within 5 Å of the antibody binding interface was analyzed using Molecular Mechanics Poisson-Boltzmann Surface Area with a per-residue energy decomposition analysis. Our analysis suggests that rocatinlimab and amlitelimab directly inhibit OX40-OX40L interactions by physically blocking the cognate OX40-OX40L interface through steric occlusion, whereas telazorlimab disrupts a critical OX40-OX40L bond. Together, this work provides molecular characterization of the epitopes of OX40- and OX40L-targeted biologics emerging in dermatology.
Insights
Computational modeling revealed how OX40-targeting antibodies rocatinlimab and telazorlimab, and OX40L-targeting amlitelimab, work. These biologics disrupt atopic dermatitis by blocking key interactions between OX40 and OX40L immune molecules.
Area of Science:
- Immunology
- Dermatology
- Computational Biology
Background:
- Atopic dermatitis is a chronic inflammatory skin condition affecting millions globally.
- Immune checkpoint molecules OX40 and OX40L play a crucial role in atopic dermatitis pathogenesis.
- Emerging biologics targeting OX40 and OX40L show promise in treating the condition.
Purpose of the Study:
- To elucidate the molecular mechanisms by which OX40- and OX40L-targeting antibodies treat atopic dermatitis.
- To characterize the binding epitopes and interaction interfaces of rocatinlimab, telazorlimab, and amlitelimab.
- To understand how these antibodies disrupt OX40-OX40L signaling pathways.
Main Methods:
- Utilized computational modeling to predict antibody-protein co-complexes.
- Characterized antibody-protein interaction interfaces.
- Employed MM-PBSA with per-residue energy decomposition to analyze binding free energies.
Main Results:
- Rocatinlimab and amlitelimab were predicted to inhibit OX40-OX40L interactions via steric occlusion.
- Telazorlimab was predicted to disrupt a critical bond within the OX40-OX40L interaction.
- Identified specific residue-residue interactions crucial for antibody binding and signaling disruption.
Conclusions:
- Provided molecular insights into the epitopes targeted by OX40/OX40L biologics in atopic dermatitis.
- Clarified the distinct mechanisms of action for rocatinlimab, telazorlimab, and amlitelimab.
- This research aids in understanding and developing novel immunotherapies for inflammatory skin diseases.
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