抗 PD-1 抗体能够使部分患者获得持久的完全缓解，从而彻底改变了癌症免疫疗法。目前的研究工作正在尝试识别生物标志物和合适的组合伙伴，以预测或进一步提高免疫检查点抑制剂的活性。抗体-细胞因子融合物是一类药物，具有增强其他免疫疗法的抗癌特性的潜力。域外 A-纤连蛋白 (EDA-FN) 在大多数实体瘤和血液肿瘤中表达，但在健康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点。在这项工作中，我们描述了一种新型基于白细胞介素 7 的靶向 EDA-FN 的融合蛋白（称为 F8(scDb)-IL7）的生成和表征。该产品由与人 IL-7 融合的单链双抗体 (scDb) 形式的 FN 选择性剪接 EDA 特异性的 F8 抗体组成。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，该产品显着增加 CD8 T 细胞上 T 细胞因子 1 (TCF-1) 的表达。 TCF-1 已成为影响肿瘤免疫反应的持久性和效力的关键转录因子。在临床前癌症模型中，F8(scDb)-IL7 表现出强大的单药活性，与抗 PD-1 联合用药可根除肉瘤病变。我们的结果为探索 F8(scDb)-IL7 与抗 PD 联合用药提供了理论基础。 -1 抗体用于治疗癌症患者。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。不得商业再利用。请参阅权利和权限。英国医学杂志出版。

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.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.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.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.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.