Department I of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
PLoS One. 2012;7(9):e44482. doi: 10.1371/journal.pone.0044482. Epub 2012 Sep 18.
Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30(+) Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer.
霍奇金氏病的成功免疫疗法目前受到侵袭性淋巴瘤浸润免疫细胞显著无反应性的阻碍。为了动员适应性和先天免疫细胞进行抗肿瘤攻击，我们将促炎细胞因子 IL2 和 IL12 融合到抗 CD30 scFv 抗体中，制成双细胞因子融合蛋白，使两种细胞因子在淋巴瘤病变中的恶性 CD30(+)霍奇金/里德-斯特恩伯格（Hodgkin/Reed-Sternberg）细胞中聚集。与靶向 IL2 或 IL12 单独应用相比，肿瘤靶向的 IL12-IL2 融合蛋白在激活静止 T 细胞以扩增和分泌促炎细胞因子方面更具优势。NK 细胞也被双细胞因子蛋白激活，分泌 IFN-γ 并溶解靶细胞。当将肿瘤靶向的 IL12-IL2 通过静脉注射应用于具有已建立的抗原阳性肿瘤的免疫功能正常的小鼠时，它会在肿瘤部位聚集并诱导肿瘤消退。数据表明，通过双细胞因子抗体融合蛋白可以将两种细胞因子同时靶向到特定的组织中，实现时空同时靶向。在 IL12 和 IL2 的情况下，这产生了更好的抗肿瘤疗效，这意味着在与癌症作斗争中，有策略地调动更广泛的免疫细胞反应。
