PDF(Pubmed)
Abstract：
BACKGROUND: Anti-PD-1 antibodies have revolutionized cancer immunotherapy due to their ability to induce long-lasting complete remissions in a proportion of patients. Current research efforts are attempting to identify biomarkers and suitable combination partners to predict or further improve the activity of immune checkpoint inhibitors. Antibody-cytokine fusions are a class of pharmaceuticals that showed the potential to boost the anticancer properties of other immunotherapies. Extradomain A-fibronectin (EDA-FN), which is expressed in most solid and hematological tumors but is virtually undetectable in healthy adult tissues, is an attractive target for the delivery of cytokine at the site of the disease.
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.
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.
摘要：
背景：抗PD-1抗体已经彻底改变了癌症免疫疗法，因为它们能够在一定比例的患者中诱导持久的完全缓解。当前的研究努力正在尝试鉴定生物标志物和合适的组合伙伴以预测或进一步改善免疫检查点抑制剂的活性。抗体-细胞因子融合是一类显示出增强其他免疫疗法的抗癌特性的潜力的药物。外生A-纤连蛋白（EDA-FN），它在大多数实体和血液肿瘤中表达，但在健康的成人组织中几乎检测不到，是在疾病部位递送细胞因子的有吸引力的靶标。
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。
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。
