Construction and stable gene expression of AGR2xPD1 bi-specific antibody that enhances attachment between T-Cells and lung tumor cells, suppress tumor cell migration and promoting CD8 expression in cytotoxic T-cells.
Construction and stable gene expression of AGR2xPD1 bi-specific antibody that enhances attachment between T-Cells and lung tumor cells, suppress tumor cell migration and promoting CD8 expression in cytotoxic T-cells.
复制标题
AGR2xPD1双特异性抗体的构建和稳定基因表达，增强T细胞与肺肿瘤细胞之间的附着，抑制肿瘤细胞迁移并促进细胞毒性T细胞中CD8的表达
DOI：
10.1016/j.jsps.2022.11.007
复制
发表时间：
2023-01
影响因子：
4.1
通讯作者：
Zhao, Bo
中科院分区：
文献类型：
--
作者：
Roy, Debmalya;Liu, Guo-Song;Wang, Aru Zeling;Zhou, Bingjie;Yunus, Fakhar-Un-Nisa;Raza, Ghulam;Merugu, Siva Bharath;Mashausi, Dhahiri Saidi;Li, Dawei;Zhao, Bo
关键词：
过去二十年来，开发先进、强效双特异性抗体 (BsAb) 的临床试验数量持续大幅增加，具有多个靶点，以提高单克隆抗体 (mAb) 治疗具有多个决定因素或广泛表达靶点的疾病的疗效或组织特异性。在本研究中，我们设计并合成了针对细胞外 AGR2（一种旁分泌信号）和 PD1（一种免疫检查点蛋白）的 BsAb AGR2xPD1。我们的设计旨在利用 AGR2 结合来指导 PD1 靶向 AGR2+癌症。我们使用这种结构通过克隆选择的高表达稳定 293F 细胞系来生产 AGR2xPD1 BsAb。在 T 细胞-肿瘤细胞共培养系统中应用这种 BsAb 表明，用这种 BsAb 靶向 PD1 和 AGR2 会诱导 TALL-104（CD8+T 淋巴细胞）细胞附着到共培养的 H460 AGR2+ 肺肿瘤细胞上，并显着减少 H460 细胞的迁移。 AGR2+H460 共培养系统中的 AGR2xPD1 BsAb 处理也协同增强了 CD8 和 IFNγ 的 T 细胞表达。 AGR2 表达阴性 WI38 细胞的这些影响显着降低。我们的结果表明，AGR2xPD1 BsAb 可能是一种潜在的治疗剂，通过阻断 AGR2 旁分泌信号传导以降低肿瘤存活率，并将细胞毒性 T 细胞重新定向为 AGR2+ 癌细胞，从而为治疗 AGR2+ 癌症提供更好的实体瘤靶向和协同功效。
There has been a substantial and consistent rise in the number of clinical trials to develop advanced and potent bispecific antibodies (BsAb) over the past two decades with multiple targets to improve the efficacy or tissue specificity of monoclonal antibodies (mAb) treatment for diseases with multiple determining factors or widely-expressed targets. In this study, we designed and synthesized BsAb AGR2xPD1 targeting extracellular AGR2, a paracrine signal, and PD1, an immune checkpoint protein. Our design is intended to use AGR2 binding to guide PD1 targeting for AGR2+cancer. We used this construction to produce AGR2xPD1 BsAb by generating clonally selected stable 293F cell line with high expression. Applying this BsAb in a T cell-Tumor cell co-culture system showed that targeting both PD1 and AGR2 with this BsAb induces the attachment of TALL-104 (CD8+T-lymphocytes) cells onto co-cultured H460 AGR2+ Lung tumor cells and significantly reduces migration of H460 cells. T-cell expression of CD8 and IFNγ is also synergistically enhanced by the AGR2xPD1 BsAb treatment in the AGR2+H460 co-culture system. These effects are significantly reduced with AGR2 expression negative WI38 cells. Our results demonstrate that the AGR2xPD1 BsAb could be a potential therapeutic agent to provide better solid tumor targeting and synergetic efficacy for treating AGR2+ cancer by blocking AGR2 paracrine signaling to reduce tumor survival, and redirecting cytotoxic T-cells into AGR2+ cancer cells.
登录
查看更多内容
影响因子：
5.3
作者：
Cao M;Wang C;Chung WK;Motabar D;Wang J;Christian E;Lin S;Hunter A;Wang X;Liu D
通讯作者：
Liu D
影响因子：
7
作者：
Pohler, E;Craig, AL;Hupp, TR
通讯作者：
Hupp, TR
影响因子：
5
作者：
Li L;Deng L;Meng X;Gu C;Meng L;Li K;Zhang X;Meng Y;Xu W;Zhao L;Chen J;Zhu Z;Huang H
通讯作者：
Huang H
DOI：
10.1016/j.bbamcr.2020.118920
发表时间：
2021-03-01
影响因子：
5.1
作者：
Fessart, Delphine;de Barbeyrac, Claire;Delom, Frederic
通讯作者：
Delom, Frederic
Anterior Gradient-2 单克隆抗体通过上调 p53 通路抑制肺癌生长和转移，且不产生任何毒理学作用：临床前研究
影响因子：
9.7
作者：
Negi, Hema;Merugu, Siva Bharath;Li, Dawei
通讯作者：
Li, Dawei