Novel humanized monoclonal antibodies against ROR1 for cancer therapy

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-08-13 DOI:10.1186/s12943-024-02075-y
Rong Wei, Xun Liao, Jiao Li, Xiaoyu Mu, Yue Ming, Yong Peng
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Abstract

Overexpression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) contributes to cancer cell proliferation, survival and migration, playing crucial roles in tumor development. ROR1 has been proposed as a potential therapeutic target for cancer treatment. This study aimed to develop novel humanized ROR1 monoclonal antibodies and investigate their anti-tumor effects. ROR1 expression in tumor tissues and cell lines was analyzed by immunohistochemistry and flow cytometry. Antibodies from mouse hybridomas were humanized by the complementarity-determining region (CDR) grafting technique. Surface plasmon resonance spectroscopy, ELISA assay and flow cytometry were employed to characterize humanized antibodies. In vitro cellular assay and in vivo mouse experiment were conducted to comprehensively evaluate anti-tumor activity of these antibodies. ROR1 exhibited dramatically higher expression in lung adenocarcinoma, liver cancer and breast cancer, and targeting ROR1 by short-hairpin RNAs significantly inhibited proliferation and migration of cancer cells. Two humanized ROR1 monoclonal antibodies were successfully developed, named h1B8 and h6D4, with high specificity and affinity to ROR1 protein. Moreover, these two antibodies effectively suppressed tumor growth in the lung cancer xenograft mouse model, c-Myc/Alb-cre liver cancer transgenic mouse model and MMTV-PyMT breast cancer mouse model. Two humanized monoclonal antibodies targeting ROR1, h1B8 and h6D4, were successfully developed and exhibited remarkable anti-tumor activity in vivo.
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用于癌症治疗的新型人源化 ROR1 单克隆抗体
受体酪氨酸激酶样孤儿受体 1(ROR1)的过度表达有助于癌细胞的增殖、存活和迁移,在肿瘤发生发展过程中起着至关重要的作用。ROR1 已被认为是癌症治疗的潜在靶点。本研究旨在开发新型人源化 ROR1 单克隆抗体并研究其抗肿瘤作用。通过免疫组化和流式细胞术分析了肿瘤组织和细胞系中 ROR1 的表达。通过互补决定区(CDR)嫁接技术对小鼠杂交瘤中的抗体进行了人源化处理。采用表面等离子体共振光谱法、ELISA 检测法和流式细胞仪来表征人源化抗体。通过体外细胞实验和体内小鼠实验,全面评估了这些抗体的抗肿瘤活性。ROR1在肺腺癌、肝癌和乳腺癌中的表达量显著升高,短发夹RNA靶向ROR1能明显抑制癌细胞的增殖和迁移。研究人员成功开发了两种人源化的 ROR1 单克隆抗体,分别命名为 h1B8 和 h6D4,它们对 ROR1 蛋白具有高度的特异性和亲和性。此外,这两种抗体还能有效抑制肺癌异种移植小鼠模型、c-Myc/Alb-cre肝癌转基因小鼠模型和MMTV-PyMT乳腺癌小鼠模型的肿瘤生长。两种靶向 ROR1 的人源化单克隆抗体(h1B8 和 h6D4)研制成功,并在体内表现出显著的抗肿瘤活性。
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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