Lu Hong-Min, Fu Yu-Jie, Liu Ning, Xia Wu-Yan, Chen Hai-Yan, Liu Meng-Yao, Li Lin-Feng, Gao Jian-Xin
The State Key Laboratory of Oncogenes and Related Genes, and The Laboratory of Tumorigenesis and Immunity, Renji-Med X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, China.
Department of Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200127, China.
Am J Cancer Res. 2022 Jan 15;12(1):265-279. eCollection 2022.
There are numerous antibodies used for cancer therapy in clinic, but they are essentially less efficacy than expected. None of them has tumor-specific and broad-spectral properties. PIWIL2-like (PL2L) protein 60 (PL2L60) is a product of alienated activation of gene, and has been found to be specifically and widely expressed in various types of cancers, including hematopoietic and solid ones. Current study aims to investigate whether a monoclonal antibody (mAb) to PL2L60 has both tumor-specific and broad-spectral properties, which can be used universally to treat various types of cancers. The expression of PL2L60 protein in the cell surface and cytoplasm were determined in a panel of human and mouse tumor cell lines by flow cytometry, immunofluorescent microscopy and Western Blotting. The apoptosis and the cell cycle arrest of the tumor cells treated with mAb KAO3 were evaluated by flow cytometry. The tumorigenesis of the mAb KAO3-pretreated tumor cells was determined by tumor incidence and tumor size, and the efficacy of mAb KAO3 treatment on tumor growth in tumors-bearing mice were kinetically evaluated. Complement-dependent cytotoxicity (CDC) assay was used to determine the capacity of mAb KAO3 to kill tumor cells. Treatment of human or mouse tumor cells from hematopoietic or solid tumors with mAb KAO3 at the time of inoculation efficiently inhibited tumorigenesis in the severe combined immunodeficient (SCID) mice. Moreover, injection of mAb KAO3 into established tumors significantly inhibited their growth, and prolonged survival of the tumor-bearing mice, including lymphoma, breast cancer, lung cancer and cervical cancer. The efficacy of mAb KAO3 treatment is likely associated with its binding to PL2L60 expressed on tumor cell surface, which may lead to cancer cell death through blocking cell cycling and/or activation of complement. In conclusion, we have identified a tumor-specific mAb to PL2L60 (KAO3), which may be used potentially to treat all the types of human cancers including from both hematopoietic and solid ones.
临床上有多种抗体用于癌症治疗，但它们的疗效实际上低于预期。它们都不具有肿瘤特异性和广谱特性。PIWIL2样（PL2L）蛋白60（PL2L60）是一个基因异化激活的产物，已被发现在包括血液系统和实体瘤在内的各种类型癌症中特异性且广泛表达。当前研究旨在探究针对PL2L60的单克隆抗体（mAb）是否具有肿瘤特异性和广谱特性，从而可普遍用于治疗各种类型的癌症。通过流式细胞术、免疫荧光显微镜和蛋白质印迹法测定了一组人和小鼠肿瘤细胞系中PL2L60蛋白在细胞表面和细胞质中的表达。通过流式细胞术评估用单克隆抗体KAO3处理的肿瘤细胞的凋亡和细胞周期阻滞情况。通过肿瘤发生率和肿瘤大小确定经单克隆抗体KAO3预处理的肿瘤细胞的致瘤性，并动态评估单克隆抗体KAO3治疗对荷瘤小鼠肿瘤生长的疗效。采用补体依赖细胞毒性（CDC）试验来确定单克隆抗体KAO3杀伤肿瘤细胞的能力。在接种时用单克隆抗体KAO3处理来自血液系统或实体瘤的人或小鼠肿瘤细胞，可有效抑制严重联合免疫缺陷（SCID）小鼠的肿瘤发生。此外，向已形成的肿瘤中注射单克隆抗体KAO3可显著抑制其生长，并延长荷瘤小鼠（包括淋巴瘤、乳腺癌、肺癌和宫颈癌）的生存期。单克隆抗体KAO3治疗的疗效可能与其与肿瘤细胞表面表达的PL2L60结合有关，这可能通过阻断细胞周期和/或激活补体导致癌细胞死亡。总之，我们鉴定出一种针对PL2L60的肿瘤特异性单克隆抗体（KAO3），它可能有潜力用于治疗所有类型的人类癌症，包括血液系统和实体瘤。
