A novel biopharmaceutical, consisting of the F8 mAb (specific to a splice isoform of fibronectin) simultaneously fused to both TNF and IL2, was found to react with the majority of solid tumors and hematologic malignancies in mouse and man, but not with healthy adult tissues. The product selectively localized to neoplastic lesions in vivo , as evidenced by quantitative biodistribution studies using radioiodinated protein preparations. When the potency of the cytokine payloads was matched by a single-point mutation, the resulting fusion protein (IL2-F8-TNFmut) eradicated soft-tissue sarcomas in immunocompetent mice, which did not respond to individual antibody–cytokine fusion proteins or by standard doxorubicin treatment. Durable complete responses were also observed in mice bearing CT26, C1498, and F9 tumors. The simultaneous delivery of multiple proinflammatory payloads to the cancer site conferred protective immunity against subsequent tumor challenges. A fully human homolog of IL2-F8-TNFmut, which retained selectivity similar to its murine counterpart when tested on human material, may open new clinical applications for the immunotherapy of cancer. Mol Cancer Ther; 16(11); 2442–51. ©2017 AACR .

中文翻译：

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效能匹配的双重细胞因子抗体融合蛋白用于癌症治疗

发现一种同时与TNF和IL2融合的，由F8 mAb（对纤连蛋白的剪接同工型特异）组成的新型生物药物可与小鼠和人的大多数实体瘤和血液系统恶性肿瘤反应，但不与健康的成人组织反应。该产品在体内选择性地定位于赘生性病变，这已通过使用放射性碘标记的蛋白质制剂进行的定量生物分布研究得到证明。当细胞因子有效载荷的效力与单点突变相匹配时，产生的融合蛋白（IL2-F8-TNFmut）消除了免疫力正常的小鼠中的软组织肉瘤，该肉瘤对单个抗体-细胞因子融合蛋白无反应或按标准阿霉素治疗。在携带CT26，C1498和F9肿瘤的小鼠中也观察到了持久的完全应答。将多种促炎有效载荷同时递送至癌症部位可赋予抵抗后续肿瘤挑战的保护性免疫力。IL2-F8-TNFmut的完全人类同源物，在对人类材料进行测试时，其选择性类似于鼠类对应物，其选择性可能保持不变，这可能会为癌症的免疫治疗打开新的临床应用。分子癌疗法；16（11）; 2442–51。©2017 AACR。