Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany.
Oncoimmunology. 2022 Jan 20;11(1):2028961. doi: 10.1080/2162402X.2022.2028961. eCollection 2022.
Targeting costimulatory receptors of the tumor necrosis factor superfamily (TNFSF) to activate T-cells and promote anti-tumor T-cell function have emerged as a promising strategy in cancer immunotherapy. Previous studies have shown that combining two different members of the TNFSF resulted in dual-acting costimulatory molecules with the ability to activate two different receptors either on the same cell or on different cell types. To achieve prolonged plasma half-life and extended drug disposition, we have developed novel dual-acting molecules by fusing single-chain ligands of the TNFSF to heterodimerizing Fc chains (scDuokine-Fc, scDk-Fc). Incorporating costimulatory ligands of the TNF superfamily into a scDk-Fc molecule resulted in enhanced T-cell proliferation translating in an increased anti-tumor activity in combination with a primary T-cell-activating bispecific antibody. Our data show that the scDk-Fc molecules are potent immune-stimulatory molecules that are able to enhance T-cell mediated anti-tumor responses.
靶向肿瘤坏死因子超家族（TNFSF）的共刺激受体激活 T 细胞并促进抗肿瘤 T 细胞功能已成为癌症免疫治疗的一种有前途的策略。先前的研究表明，两种不同的 TNFSF 成员的结合产生了双重作用的共刺激分子，具有在同一细胞或不同细胞类型上激活两种不同受体的能力。为了实现延长的血浆半衰期和延长的药物处置，我们通过将 TNFSF 的单链配体融合到异二聚化 Fc 链（scDuokine-Fc，scDk-Fc）中来开发新型双重作用分子。将 TNF 超家族的共刺激配体纳入 scDk-Fc 分子中可增强 T 细胞增殖，与主要的 T 细胞激活双特异性抗体联合使用可提高抗肿瘤活性。我们的数据表明，scDk-Fc 分子是有效的免疫刺激分子，能够增强 T 细胞介导的抗肿瘤反应。
