De Novo Design of Ultrahigh-Affinity Miniproteins Targeting PD-L1 for Non-Invasive Imaging: Preclinical Validation and First-in-Human Study
Zhao, L.; Zhang, F.; Yao, R.; Hao, S.; Zhang, G.; Tao, J.; Guo, G.; Li, X.; Yang, G.; Li, T.; Li, H.; Cui, S.; Wang, F.; Wang, Q.; Song, Z.; Feng, J.; Shen, B.; Yao, Y.; Guo, Y.; Zhu, H.; Hu, Y.
Show abstract
De novo protein design is becoming a powerful tool for diagnostic and therapeutic agent development. However, direct evidence remains lacking for dynamic binding of de novo designed binders both in vivo and clinical settings. PD-L1, quantified via immunohistochemistry, represents the most widely validated, utilized, and accepted biomarker for PD-1/PD-L1 therapy. Due to the spatial heterogeneity and temporal dynamics of PD-L1 expression, this molecule represents an ideal target for exploring the dynamic binding of de novo-designed binders. Herein, we report de novo-designed miniprotein PD-L1-3--an ultrahigh-affinity binder targeting the PD-1/PD-L1 interface with sub-picomolar affinity and hyper-stability. Preclinical and first-in-human studies demonstrated that this de novo-designed ultrahigh-affinity binder exhibits significantly improved binding specificity, enhanced tissue penetration, prolonged target-positive tumor retention and a favorable safety profile in vivo and in patients, enabling advanced diagnostic and therapeutic agent development.
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