RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
靶向 Siglec-E 的 Ig 结构域的双特异性抗体显示出增强的抗肿瘤效果
英文原题：A bispecific antibody targeting the Ig domains of Siglec-E displays enhanced antitumor effects.
查看英文原题
A bispecific antibody targeting the Ig domains of Siglec-E displays enhanced antitumor effects.
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中文摘要
Siglec-9是一种有前景的免疫检查点分子，靶向Siglec-9的治疗药物具有增强抗肿瘤免疫的潜力。在此，我们通过融合两个不同的羊驼源纳米抗体，生成了一种名为aSE4-1-Fc的双特异性抗体，该抗体能够以高亲和力同时靶向小鼠Siglec-9（也称为Siglec-E）的胞外Ig可变（V）集结构域和C2集结构域。体内研究显示，aSE4-1-Fc在抑制肿瘤生长/转移方面优于其组分抗体，并且使用aSE4-1-Fc阻断Siglec-E产生了保护性抗肿瘤T细胞记忆。此外，aSE4-1-Fc与抗PD-L1治疗的联合通过增强T细胞和NK细胞，极大地改善了抗肿瘤效果。综上所述，本研究强调了Siglec-9作为潜在癌症治疗靶点的重要性，证明了共同抑制Siglec-9和PD-L1的协同效应，并可能对开发具有增强治疗效果的靶向Siglec-9的工程化抗体具有重要意义。
展开英文摘要原文
Siglec-9 is a promising immune checkpoint molecule, and therapeutics targeting Siglec-9 have the potential to augment anti-tumor immunity.
Here, we generated a bispecific antibody, named as aSE4-1-Fc, by fusing two distinct alpaca derived nanobodies, which can simultaneously target the extracellular Ig variable (V)-set domain and C2-set domains of murine Siglec-9 (also known as Siglec-E) with high affinity. In vivo studies showed that aSE4-1-Fc was better than its component antibodies in inhibiting tumor growth/metastasis, and Siglec-E blockade using aSE4-1-Fc generated protective anti-tumor T cell memory.
Furthermore, the combination of aSE4-1-Fc with anti-PD-L1 therapy greatly improved the antitumor effects by augmenting both T and NK cells. Taken together, this study emphasizes the importance of Siglec-9 as a potential cancer therapeutic target, demonstrates the synergistic effect of co-inhibition of Siglec-9 and PD-L1, and may have implications for developing engineered antibodies targeting Siglec-9 with enhanced therapeutic efficacy.
论文信息
- 作者
- Zhao D、Liu M、Zeng W、Chen S、Bibi S、Wang M、Huang X、Zhu F
- 第一作者单位
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, University of Science and Technology of China, Hefei, Anhui 230001, China.China
- 通讯作者单位
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, University of Science and Technology of China, Hefei, Anhui 230001, China; Laboratory of Structural Immunology, Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; College of Medicine, Lishui University, Lishui, 323000, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China; Anhui Genebiol Biotech. LTD., Hefei, 230000, China; Biomedical Sciences and Health Laboratory of Anhui Province, University of Science & Technology of China, Hefei 230027, China; Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei 230001, China. Electronic address: jint@ustc.edu.cn.China
- 期刊
- International journal of biological macromolecules2024 Nov
- 原文标识
- PubMed 39419134 · DOI 10.1016/j.ijbiomac.2024.136635