白细胞介素-6 (IL-6) 是一种高度促炎细胞因子，参与多种炎症性疾病和癌症的病因病理学。因此，IL-6信号通路的抑制已成为治疗多种慢性疾病的一种有吸引力的治疗途径。由于 IL-6 反式信号传导被描述为 IL-6 的病理分支，因此开发了选择性抑制剂。具有增强的反式信号传导特异性和效力的下一代变体成为治疗多种疾病的绝佳候选者，同时减少了脱靶效应。然而，涉及重组蛋白生产的高度耗时且成本高昂的过程迄今为止阻碍了抗细胞因子药物在临床上的进展。在此，我们开发了 IL-6 反式信号传导抑制剂的基因治疗方式作为持续重组蛋白分泌的替代方案。通过使用 IL-6 依赖性淋巴瘤细胞系和异种移植肿瘤模型，我们证明了第二代抗 IL-6 反式信号传导治疗的卓越抑制潜力。我们使用生物发光生物标记探针比较了不同基因递送方式的效率，并观察到通过基于细胞的递送产生一致的蛋白质。当肿瘤内递送时，基因工程的 sgp130FlyRFc 分泌细胞显着降低了肿瘤负荷并增加了动物存活率，代表了临床相关基因递送应用中有待探索的有前途的治疗途径。© 2024。作者。

Interleukin-6 (IL-6) is a highly pro-inflammatory cytokine involved in the etiopathology of several inflammatory diseases and cancer. As so, the inhibition of IL-6 signaling pathways has emerged as an attractive therapeutic avenue for the treatment of several chronic diseases. Since IL-6 trans-signaling was described as the pathological branch of IL-6, selective inhibitors were developed. Next-generation variants with increased trans-signaling specificity and potency emerged as great candidates for the treatment of several diseases, with reduced off-target effects. The highly time-consuming and costly processes involving recombinant protein production, however, have hampered the progress of anti-cytokine pharmaceuticals in clinic so far. Herein, we developed gene therapeutic modalities of IL-6-trans-signaling inhibitors as alternatives for sustained recombinant protein secretion. By using an IL-6-dependent lymphoma cell line and xenograft tumor model, we demonstrated the superior inhibitory potential of second-generation anti-IL-6 trans-signaling therapeutic. We compared the efficiency of distinct gene delivery modalities using a bioluminescent biomarker probe and observed consistent protein production via cell-based delivery. When delivered intratumorally, genetically engineered sgp130FlyRFc-secreting cells significantly reduced tumor burden and increased animal survival, representing a promising therapeutic avenue to be explored in clinically relevant gene delivery applications.© 2024. The Author(s).