The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1.
The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1.
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同时靶向TGF-β和PD-L1的双特异性抗体YM 101的构建、表达和增强的抗肿瘤活性
DOI：
10.1186/s13045-021-01045-x
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发表时间：
2021-02-16
影响因子：
28.5
通讯作者：
Wu K
中科院分区：
文献类型：
--
作者：
Yi M;Zhang J;Li A;Niu M;Yan Y;Jiao Y;Luo S;Zhou P;Wu K
靶向程序性细胞死亡蛋白 1 (PD-1)/程序性死亡配体 1 (PD-L1) 轴的治疗性抗体可在多种类型的癌症中诱导有效且持久的抗肿瘤反应。然而，只有一小部分患者从抗 PD-1/PD-L1 疗法中受益。 TGF-β作为抗肿瘤免疫的负调节因子，会损害抗PD-1/PD-L1的功效并诱导耐药性。开发一种同时阻断PD-1/PD-L1和TGF-β的新治疗策略对于增强抗PD-1/PD-L1的效果并缓解耐药性具有重要价值。基于Check-BODY™技术平台，我们开发了抗TGF-β/PD-L1双特异性抗体YM101。通过 Smad-荧光素酶报告基因测定、transwell 测定、蛋白质印迹、CCK-8 和流式细胞术测定抗 TGF-β 部分的生物活性。通过 T 细胞活化测定来测量抗 PD-L1 部分的生物活性。采用EMT-6、CT26和3LL肿瘤模型研究YM101的体内抗肿瘤活性。利用RNA-seq、免疫组织化学染色和流式细胞术分析YM101对肿瘤微环境的影响。 YM101可以特异性结合TGF-β和PD-L1。体外实验表明，YM101能有效抵消TGF-β和PD-1/PD-L1通路的生物学效应，包括激活Smad信号、诱导上皮间质转化和免疫抑制。此外，体内实验表明YM101的抗肿瘤活性优于抗TGF-β和抗PD-L1单一疗法。从机制上讲，YM101促进“热肿瘤”的形成：增加肿瘤浸润淋巴细胞和树突状细胞的数量，提高M1/M2的比率，并增强T细胞中细胞因子的产生。这种正常化的肿瘤免疫微环境和增强的抗肿瘤免疫反应可能有助于 YM101 强大的抗肿瘤作用。我们的结果表明，YM101 可以同时阻断 TGF-β 和 PD-L1 通路，并且与单一疗法相比具有更优异的抗肿瘤作用。
Therapeutic antibodies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis induce potent and durable anti-tumor responses in multiple types of cancers. However, only a subset of patients benefits from anti-PD-1/PD-L1 therapies. As a negative regulator of anti-tumor immunity, TGF-β impairs the efficacy of anti-PD-1/PD-L1 and induces drug resistance. Developing a novel treatment strategy to simultaneously block PD-1/PD-L1 and TGF-β would be valuable to enhance the effect of anti-PD-1/PD-L1 and relieve drug resistance. Based on the Check-BODY™ technology platform, we developed an anti-TGF-β/PD-L1 bispecific antibody YM101. The bioactivity of the anti-TGF-β moiety was determined by Smad-luciferase reporter assay, transwell assay, western blotting, CCK-8, and flow cytometry. The bioactivity of the anti-PD-L1 moiety was measured by T cell activation assays. EMT-6, CT26, and 3LL tumor models were used to investigate the anti-tumor activity of YM101 in vivo. RNA-seq, immunohistochemical staining, and flow cytometry were utilized to analyze the effect of YM101 on the tumor microenvironment. YM101 could bind to TGF-β and PD-L1 specifically. In vitro experiments showed that YM101 effectively counteracted the biological effects of TGF-β and PD-1/PD-L1 pathway, including activating Smad signaling, inducing epithelial-mesenchymal transition, and immunosuppression. Besides, in vivo experiments indicated the anti-tumor activity of YM101 was superior to anti-TGF-β and anti-PD-L1 monotherapies. Mechanistically, YM101 promoted the formation of ‘hot tumor’: increasing the numbers of tumor infiltrating lymphocytes and dendritic cells, elevating the ratio of M1/M2, and enhancing cytokine production in T cells. This normalized tumor immune microenvironment and enhanced anti-tumor immune response might contribute to the robust anti-tumor effect of YM101. Our results demonstrated that YM101 could simultaneously block TGF-β and PD-L1 pathways and had a superior anti-tumor effect compared to the monotherapies.
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PD-1检查点途径的分子和生化方面。
DOI：
10.1056/nejmra1514296
发表时间：
2016-11-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Boussiotis VA
通讯作者：
Boussiotis VA
影响因子：
64.8
作者：
Mariathasan S;Turley SJ;Nickles D;Castiglioni A;Yuen K;Wang Y;Kadel EE III;Koeppen H;Astarita JL;Cubas R;Jhunjhunwala S;Banchereau R;Yang Y;Guan Y;Chalouni C;Ziai J;Şenbabaoğlu Y;Santoro S;Sheinson D;Hung J;Giltnane JM;Pierce AA;Mesh K;Lianoglou S;Riegler J;Carano RAD;Eriksson P;Höglund M;Somarriba L;Halligan DL;van der Heijden MS;Loriot Y;Rosenberg JE;Fong L;Mellman I;Chen DS;Green M;Derleth C;Fine GD;Hegde PS;Bourgon R;Powles T
通讯作者：
Powles T
影响因子：
8.8
作者：
Lau, Eunice Yuen Ting;Lo, Jessica;Lee, Terence Kin Wah
通讯作者：
Lee, Terence Kin Wah
影响因子：
28.5
作者：
Basher, Fahmin;Dhar, Payal;Wu, Jennifer D.
通讯作者：
Wu, Jennifer D.
影响因子：
1.6
作者：
Drees, Jeremy J.;Augustin, Lance B.;Saltzman, Daniel A.
通讯作者：
Saltzman, Daniel A.