Engineering nano‐clustered multivalent agonists to cross‐link TNF receptors for cancer therapy

Author:

Zhang Yue12,Zhao Gui12,Chen Yi‐Fang12,Zhou Shi‐Kun12,Wang Yue12,Sun Yi‐Qun12,Shen Song123,Xu Cong‐Fei123ORCID,Wang Jun124ORCID

Affiliation:

1. School of Biomedical Sciences and Engineering South China University of Technology Guangzhou International Campus Guangzhou P.R. China

2. National Engineering Research Center for Tissue Restoration and Reconstruction South China University of Technology Guangzhou P.R. China

3. Guangdong Provincial Key Laboratory of Biomedical Engineering South China University of Technology Guangzhou P.R. China

4. Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education South China University of Technology Guangzhou P.R. China

Abstract

AbstractTumor necrosis factor receptors (TNFRs) are promising targets for cancer therapy. However, activating their downstream signaling requires cross‐linking of TNFRs. Herein, to devise strong agonists of TNFRs, ligands targeting TNFRs, such as OX40L and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), were fused with a multivalent protein scaffold (MV) to prepare multivalent agonists for cross‐linking TNFRs. The nano‐clustered multivalent‐OX40L (MV‐OX40L) and MV‐TRAIL could promote T cell activation and directly induce tumor cell apoptosis. Moreover, to develop a universal nano‐adaptor for the rapid preparation of multivalent agonists of different TNFRs, the Fc receptor that could immobilize antibodies was fused with MV to prepare MV‐FcR, which could multimerize commercial agonist antibodies targeting TNFRs, such as anti‐OX40 antibody (αOX40). Simply incubating αOX40 with MV‐FcR could prepare MV‐αOX40 to enhance its antitumor efficacy. In addition, MV‐FcR could multimerize with other therapeutic antibodies, such as anti‐PD‐L1 antibody, to enhance their valency. This study provides a promising strategy for engineering multivalent antitumor protein drugs.

Funder

National Natural Science Foundation of China

Fundamental Research Funds for the Central Universities

Publisher

Wiley

Subject

General Medicine,General Chemistry

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