Preclinical evaluation of IL2-based immunocytokines supports their use in combination with dacarbazine, paclitaxel and TNF-based immunotherapy
Preclinical evaluation of IL2-based immunocytokines supports their use in combination with dacarbazine, paclitaxel and TNF-based immunotherapy
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基于 IL2 的免疫细胞因子的临床前评估支持其与达卡巴嗪、紫杉醇和基于 TNF 的免疫疗法联合使用
DOI：
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
D. Neri
中科院分区：
文献类型：
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作者：
Francesca Pretto;G. Elia;N. Castioni;D. Neri
抗体-细胞因子融合蛋白(“免疫细胞因子”)代表了一类很有前途的武装抗体产品，它允许在肿瘤部位选择性地输送有效的促炎有效载荷。基于抗体的白介素2(IL2)选择性递送对于转移性黑色素瘤的治疗特别有吸引力，这种细胞因子获得了美国食品和药物管理局(FDA)的上市批准。我们使用K1735M2小鼠黑色素瘤免疫活性同基因模型研究了F8-IL2的治疗活性，F8-IL2是一种基于Diabody形式的F8抗体的免疫细胞因子，与人IL2融合。静脉给药后，F8-IL2在体内选择性地定位于肿瘤部位，并介导肿瘤生长迟缓，与紫杉醇或达卡巴津联合使用可增强这一作用。与作为单一药物使用的细胞毒药物相比，联合治疗导致了更有效的肿瘤生长抑制，而没有额外的毒性。免疫渗入分析显示，联合用药24小时后，CD4+T细胞显著积聚。F8-IL2和L19-IL2的融合蛋白分别针对纤维连接蛋白的A域和B域的选择性剪接，并与基于肿瘤坏死因子的免疫细胞因子相结合。联合治疗优于单独的免疫细胞因子的作用，并能够在一次瘤内注射后根除肿瘤病变，这是一种临床上用于治疗IIIC期黑色素瘤的方法。总的来说，这些数据强化了将基于IL2的免疫细胞因子与细胞毒剂或基于肿瘤坏死因子的免疫疗法结合使用来治疗黑色素瘤患者的理论基础。
Antibody-cytokine fusion proteins (“immunocytokines”) represent a promising class of armed antibody products, which allow the selective delivery of potent pro-inflammatory payloads at the tumor site. The antibody-based selective delivery of interleukin-2 (IL2) is particularly attractive for the treatment of metastatic melanoma, an indication for which this cytokine received marketing approval from the US Food and drug administration. We used the K1735M2 immunocompetent syngeneic model of murine melanoma to study the therapeutic activity of F8–IL2, an immunocytokine based on the F8 antibody in diabody format, fused to human IL2. F8–IL2 was shown to selectively localize at the tumor site in vivo, following intravenous administration, and to mediate tumor growth retardation, which was potentiated by the combination with paclitaxel or dacarbazine. Combination treatment led to a substantially more effective tumor growth inhibition, compared to the cytotoxic drugs used as single agents, without additional toxicity. Analysis of the immune infiltrate revealed a significant accumulation of CD4+ T cells 24 h after the administration of the combination. The fusion proteins F8–IL2 and L19–IL2, specific to the alternatively spliced extra domain A and extra domain B of fibronectin respectively, were also studied in combination with tumor necrosis factor (TNF)-based immunocytokines. The combination treatment was superior to the action of the individual immunocytokines and was able to eradicate neoplastic lesions after a single intratumoral injection, a procedure that is being clinically used for the treatment of Stage IIIC melanoma. Collectively, these data reinforce the rationale for the use of IL2-based immunocytokines in combination with cytotoxic agents or TNF-based immunotherapy for the treatment of melanoma patients.
影响因子：
45.3
作者：
King, DM;Albertini, MR;Sondel, P
通讯作者：
Sondel, P