A Polyvalent Peptide CD40 Nanoagonist for Targeted Modulation of Dendritic Cells and Amplified Cancer Immunotherapy.

Targeted immunomodulation through biomolecule-based nanostructures, especially to dendritic cells (DCs), holds great promise for effective cancer therapy. However, construction of high-performance agonist by mimicking natural ligand to activate immune cell signaling is a great challenge so far. Here, a peptide-based nanoagonist toward CD40 (PVA-CD40) with preorganized interfacial topological structure that activates lymph node DCs efficiently and persistently, achieving amplified immune therapeutic efficacy is described. The on-site fabrication of PVA-CD40 is realized through the click conjugation of two functional peptides including the "CD40 anchoring arm" and the "assembly-driving motor." The resultant polyvalent interface rapidly triggers the receptor oligomerization and downstream signaling. Strikingly, one shot administration of PVA-CD40 elicits maturation period of DCs up to 2.3-fold comparing to that of CD40 antibody. Finally, combining the PVA-CD40 with anti-PD-1 antibody results in subsequent inhibition of tumor growth in both B16F10 and 4T1 mice tumor models with survival rate up to 37%, while none of the mice survives in the clinically relevant CD40 mAb and anti-PD-1 combination-treated group. It is envisioned that the fabrication of antibody-like superstructures in vivo provides an efficient platform for modulating the duration of immune response to achieve optimal therapeutic efficacy. © 2022 Wiley-VCH GmbH.

Citation

Muhetaerjiang Mamuti, Yi Wang, Yong-Dan Zhao, Jia-Qi Wang, Jie Wang, Yan-Lei Fan, Wu-Yi Xiao, Da-Yong Hou, Jia Yang, Rui Zheng, Hong-Wei An, Hao Wang. A Polyvalent Peptide CD40 Nanoagonist for Targeted Modulation of Dendritic Cells and Amplified Cancer Immunotherapy. Advanced materials (Deerfield Beach, Fla.). 2022 Jun;34(24):e2109432

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PMID: 35426184

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