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Bifunctional Fusion Proteins Derived from Tumstatin and 4-1BBL for Targeted Cancer Therapy
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-12-19 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b01190 Chao Sun 1 , Dongyang He 1 , Chao Ma 1 , Zhenyue Gao 1 , Yijun Chen 1 , Shuzhen Wang 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-12-19 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b01190 Chao Sun 1 , Dongyang He 1 , Chao Ma 1 , Zhenyue Gao 1 , Yijun Chen 1 , Shuzhen Wang 1
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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.
中文翻译：
Tumstatin和4-1BBL衍生的双功能融合蛋白用于靶向癌症治疗
抗血管生成和免疫疗法的治疗效用已在临床上得到证明，癌症患者已从各自的疗法中受益。考虑到两种治疗策略的结合可以进一步提高疗效，本研究构建了重组人4-1BBL /肿瘤抑素融合蛋白（rh4TFP）文库，以靶向血管生成和T淋巴细胞活化，其中内源性片段血管生成抑制剂肿瘤抑素和T淋巴细胞共刺激4-1BBL与不同的接头偶联。比较不同的组合后，发现rh4TFP-2对潜在的抗血管生成免疫疗法有希望。一方面，rh4TFP-2抑制人脐静脉内皮细胞的增殖和迁移，表现出类似于肿瘤抑素的抗血管生成活性。另一方面，rh4TFP-2导致T淋巴细胞活化显着增加，从而释放IL-2和IFN-γ，显示4-1BBL激活T淋巴细胞。此外，在带有B16F10黑色素瘤的小鼠模型中，施用rh4TFP-2抑制了肿瘤生长并延长了生存期。综上所述，本研究提供了一种使用双功能融合蛋白靶向靶向血管生成和T淋巴细胞活化进行癌症治疗的新方法。
更新日期：2018-12-19
中文翻译：
Tumstatin和4-1BBL衍生的双功能融合蛋白用于靶向癌症治疗
抗血管生成和免疫疗法的治疗效用已在临床上得到证明，癌症患者已从各自的疗法中受益。考虑到两种治疗策略的结合可以进一步提高疗效，本研究构建了重组人4-1BBL /肿瘤抑素融合蛋白（rh4TFP）文库，以靶向血管生成和T淋巴细胞活化，其中内源性片段血管生成抑制剂肿瘤抑素和T淋巴细胞共刺激4-1BBL与不同的接头偶联。比较不同的组合后，发现rh4TFP-2对潜在的抗血管生成免疫疗法有希望。一方面，rh4TFP-2抑制人脐静脉内皮细胞的增殖和迁移，表现出类似于肿瘤抑素的抗血管生成活性。另一方面，rh4TFP-2导致T淋巴细胞活化显着增加，从而释放IL-2和IFN-γ，显示4-1BBL激活T淋巴细胞。此外，在带有B16F10黑色素瘤的小鼠模型中，施用rh4TFP-2抑制了肿瘤生长并延长了生存期。综上所述，本研究提供了一种使用双功能融合蛋白靶向靶向血管生成和T淋巴细胞活化进行癌症治疗的新方法。
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