Tumor 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 ...Tumor 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 incubatingαOX40 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.展开更多
基金National Key R&D Program of China,Grant/Award Number:2022YFB3808100National Natural Science Foundation of China,Grant/Award Numbers:32271442,52130301,82072048+2 种基金Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2022B1515020025Science and Technology Program of Guangzhou,China,Grant/Award Number:202103030004Fundamental Research Funds for the Central Universities,Grant/Award Number:2022ZYGXZR102。
文摘Tumor 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 incubatingαOX40 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.
