Antagonist anti-LIF antibody derived from naive human scFv phage library inhibited tumor growth in mice.

IF 2.9 4区 医学 Q3 IMMUNOLOGY BMC Immunology Pub Date : 2024-08-22 DOI:10.1186/s12865-024-00636-w
Shengyan Zhao, Han Deng, Ying Lu, Yiran Tao, David Li, Xiaohua Jiang, Xian Wei, Xiaofeng Chen, Fanxin Ma, Yuxi Wang, Lantu Gou, Jinliang Yang
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Abstract

Background: Leukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g. pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer) and promotes cancer cell proliferation, migration, invasion, and differentiation. Moreover, the overexpression of LIF correlates with poor clinicopathological characteristics. Therefore, we hypothesized that LIF could be a promising target for the treatment of cancer. In this work, we developed the antagonist antibody 1G11 against LIF and investigated its anti-tumor mechanism and its therapeutic efficacy in mouse models.

Results: A series of single-chain variable fragments (scFvs) targeting LIF were screened from a naive human scFv phage library. These scFvs were reconstructed in complete IgG form and produced by the mammalian transient expression system. Among the antibodies, 1G11 exhibited the excellent binding activity to human, cynomolgus monkey and mouse LIF. Functional analysis demonstrated 1G11 could block LIF binding to LIFR and inhibit the intracellular STAT3 phosphorylation signal. Interestingly, 1G11 did not block LIF binding to gp130, another LIF receptor that is involved in forming the receptor complex together with LIFR. In vivo, intraperitoneal administration of 1G11 inhibited tumor growth in CT26 and MC38 models of colorectal cancer. IHC analysis demonstrated that p-STAT3 and Ki67 were decreased in tumor tissue, while c-caspase 3 was increased. Furthermore, 1G11 treatment improves CD3+, CD4 + and CD8 + T cell infiltration in tumor tissue.

Conclusions: We developed antagonist antibodies targeting LIF/LIFR signaling pathway from a naive human scFv phage library. Antagonist anti-LIF antibody exerts antitumor effects by specifically reducing p-STAT3. Further studies revealed that anti-LIF antibody 1G11 increased immune cell infiltration in tumor tissues.

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从天真人类 scFv 噬菌体库中提取的拮抗剂抗 LIF 抗体抑制了小鼠的肿瘤生长。
背景:白血病抑制因子(LIF)是 IL-6 细胞因子家族的多功能成员,它通过与细胞表面由 LIFR 和 gp130 组成的异二聚体结合激活下游信号通路。以往的研究表明,LIF 在多种肿瘤组织(如胰腺癌、乳腺癌、前列腺癌和结直肠癌)中高表达,并促进癌细胞增殖、迁移、侵袭和分化。此外,LIF 的过表达与不良的临床病理特征相关。因此,我们推测 LIF 可能是治疗癌症的一个有前途的靶点。在这项工作中,我们开发了针对 LIF 的拮抗剂抗体 1G11,并在小鼠模型中研究了其抗肿瘤机制和疗效:结果:从天真的人类 scFv 噬菌体文库中筛选出了一系列靶向 LIF 的单链可变片段(scFvs)。这些 scFvs 被重构为完整的 IgG 形式,并由哺乳动物瞬时表达系统生产。在这些抗体中,1G11 与人类、猴和小鼠 LIF 的结合活性极佳。功能分析表明,1G11 能阻断 LIF 与 LIFR 的结合,抑制细胞内 STAT3 磷酸化信号。有趣的是,1G11 并不阻断 LIF 与 gp130 的结合,gp130 是另一种 LIF 受体,与 LIFR 一起参与形成受体复合物。在体内,腹腔注射 1G11 可抑制 CT26 和 MC38 结直肠癌模型的肿瘤生长。IHC分析表明,肿瘤组织中的p-STAT3和Ki67降低,而c-caspase 3升高。此外,1G11治疗可改善肿瘤组织中CD3+、CD4+和CD8+T细胞的浸润:我们从天真人类scFv噬菌体文库中开发出了靶向LIF/LIFR信号通路的拮抗剂抗体。拮抗剂抗 LIF 抗体通过特异性降低 p-STAT3 发挥抗肿瘤作用。进一步研究发现,抗LIF抗体1G11增加了肿瘤组织中免疫细胞的浸润。
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来源期刊
BMC Immunology
BMC Immunology 医学-免疫学
CiteScore
5.50
自引率
0.00%
发文量
54
审稿时长
1 months
期刊介绍: BMC Immunology is an open access journal publishing original peer-reviewed research articles in molecular, cellular, tissue-level, organismal, functional, and developmental aspects of the immune system as well as clinical studies and animal models of human diseases.
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