METHODS: In this work, we describe the generation and characterization of a novel interleukin-7-based fusion protein targeting EDA-FN termed F8(scDb)-IL7. The product consists of the F8 antibody specific to the alternatively spliced EDA of FN in the single-chain diabody (scDb) format fused to human IL-7.
RESULTS: F8(scDb)-IL7 efficiently stimulates human peripheral blood mononuclear cells in vitro. Moreover, the product significantly increases the expression of T Cell Factor 1 (TCF-1) on CD8+T cells compared with an IL2-fusion protein. TCF-1 has emerged as a pivotal transcription factor that influences the durability and potency of immune responses against tumors. In preclinical cancer models, F8(scDb)-IL7 demonstrates potent single-agent activity and eradicates sarcoma lesions when combined with anti-PD-1.
CONCLUSIONS: Our results provide the rationale to explore the combination of F8(scDb)-IL7 with anti-PD-1 antibodies for the treatment of patients with cancer.
方法:在这项工作中,我们描述了一种新的基于白细胞介素7的融合蛋白的产生和表征,该融合蛋白靶向EDA-FN,称为F8(scDb)-IL7。产物由与人IL-7融合的单链双抗体(scDb)形式的FN的选择性剪接EDA特异性的F8抗体组成。
结果:F8(scDb)-IL7在体外有效刺激人外周血单核细胞。此外,与IL2融合蛋白相比,该产物显着增加CD8T细胞上T细胞因子1(TCF-1)的表达。TCF-1已成为影响抗肿瘤免疫应答的持久性和效力的关键转录因子。在临床前癌症模型中,当与抗PD-1组合时,F8(scDb)-IL7表现出有效的单剂活性并根除肉瘤病变。
结论:我们的结果为探索F8(scDb)-IL7与抗PD-1抗体联合治疗癌症患者提供了理论基础。