Bifunctional Fusion Proteins Derived from Tumstatin and 4-1BBL for Targeted Cancer Therapy.
Bifunctional Fusion Proteins Derived from Tumstatin and 4-1BBL for Targeted Cancer Therapy.
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DOI：
10.1021/acs.molpharmaceut.8b01190
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发表时间：
2019-02
影响因子：
4.9
通讯作者：
Chao Sun;Dongyang He;Chao Ma;Zhenyue Gao;Yijun Chen;Shuzhen Wang
中科院分区：
文献类型：
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作者：
Chao Sun;Dongyang He;Chao Ma;Zhenyue Gao;Yijun Chen;Shuzhen Wang
抗血管生成和免疫疗法的治疗效用已在临床中得到证实，癌症患者已从各自的治疗中受益。鉴于两种治疗策略的结合可能进一步提高疗效，本研究构建了重组人4-1BBL/tumstatin融合蛋白（rh4TFP）文库，以靶向血管生成和T淋巴细胞激活，其中内源性血管生成抑制剂tumstatin和T淋巴细胞共刺激4-1BBL的片段通过不同的接头偶联。在比较不同的组合后，发现rh4TFP-2在潜在的抗血管生成免疫治疗中表现出了希望。一方面，rh4TFP-2抑制人脐静脉内皮细胞的增殖和迁移，表现出与tumstatin类似的抗血管生成活性。另一方面，rh4TFP-2导致T淋巴细胞活化显着增加，以释放IL-2和IFN-γ，显示4-1BBL的T淋巴细胞活化。此外，在 B16F10 黑色素瘤小鼠模型中，给予 rh4TFP-2 可以抑制肿瘤生长并延长生存期。总而言之，本研究提供了一种使用双功能融合蛋白靶向血管生成和 T 淋巴细胞激活来治疗癌症的新方法。
The therapeutic utilities of antiangiogenesis and immunotherapy have been proven in clinics, and cancer patients have benefited from respective therapy. Given that the combination of both therapeutic strategies may further improve the effectiveness, a recombinant human 4-1BBL/tumstatin fusion protein (rh4TFP) library was constructed in the present study to target both angiogenesis and T lymphocyte activation, in which the fragments of an endogenous angiogenesis inhibitor tumstatin and a T lymphocyte costimulatory 4-1BBL are coupled with different linkers. After comparison of different combinations, rh4TFP-2 was found to show a promise on potential antiangiogenic immunotherapy. On one hand, rh4TFP-2 inhibited proliferation and migration of human umbilical vein endothelial cells, exhibiting the antiangiogenic activity similar to tumstatin. On the other hand, rh4TFP-2 led to significant increase of T lymphocyte activation for the release of IL-2 and IFN-γ, showing the T lymphocyte activation by 4-1BBL. Moreover, administration of rh4TFP-2 suppressed tumor growth and prolonged survival in a B16F10 melanoma-bearing mouse model. Taken together, the present study provides a new approach of using bifunctional fusion proteins to target both angiogenesis and T lymphocyte activation for cancer therapy.