Mueller Nico, de la Roche Marc Andrew, de la Roche Maike
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom.
Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
Immunother Adv. 2025 Apr 25;5(1):ltaf017. doi: 10.1093/immadv/ltaf017. eCollection 2025.
Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a transcriptional target gene of the Wnt signalling pathway, is overexpressed in multiple cancers, including colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B acute lymphoblastic leukaemia (pre-B ALL) and has emerged as a promising therapeutic target. Here, we reflect on the bottom-up development of a novel α-LGR5 therapeutic antibody we have recently reported, into a palette of LGR5-targeting immunotherapeutic modalities: antibody-drug conjugates (ADCs), bispecific T cell engagers (bispecific engagers), and chimeric antigen receptor (CAR) T cells. The α-LGR5 antibody is highly specific and accurately detects LGR5 protein expression levels, enabling its use as a prognostic biomarker for identifying LGR5 tumour types. Preclinical studies road-testing the various α-LGR5-based modalities established potent and safe elimination of LGR5-expressing cancer cells and efficacy in a mouse model of human cancer . In this review, we discuss the utility of our antibody as the building block for a novel set of immunotherapeutics and highlight the importance of matching specific α-LGR5-based therapeutic modalities to individual tumour type and patient characteristics.
富含亮氨酸重复序列的G蛋白偶联受体5（LGR5）是Wnt信号通路的一个转录靶基因，在多种癌症中过表达，包括结直肠癌（CRC）、肝细胞癌（HCC）和前B细胞急性淋巴细胞白血病（pre-B ALL），并已成为一个有前景的治疗靶点。在此，我们回顾了我们最近报道的一种新型α-LGR5治疗性抗体自下而上的研发过程，它已发展成为一系列靶向LGR5的免疫治疗方式：抗体药物偶联物（ADC）、双特异性T细胞衔接器（双特异性衔接器）和嵌合抗原受体（CAR）T细胞。α-LGR5抗体具有高度特异性，能准确检测LGR5蛋白表达水平，可作为识别LGR5肿瘤类型的预后生物标志物。对各种基于α-LGR5的治疗方式进行的临床前研究表明，在人类癌症小鼠模型中能有效且安全地清除表达LGR5的癌细胞。在这篇综述中，我们讨论了我们的抗体作为一组新型免疫治疗药物构建模块的效用，并强调了将特定的基于α-LGR5的治疗方式与个体肿瘤类型和患者特征相匹配的重要性。
