We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

中文翻译：

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针对 LGR5 的新型免疫疗法可靶向多种癌症类型。


我们开发并验证了一种针对人类 LGR5 (α-LGR5) 细胞外结构域的高度特异性、多功能抗体。 α-LGR5 可检测 >90% 的结直肠癌 (CRC)、肝细胞癌 (HCC) 和 pre-B-ALL 肿瘤细胞中的 LGR5 过表达，并用于生成抗体药物偶联物 (α-LGR5-ADC)、双特异性 T -细胞接合器（α-LGR5-BiTE）和嵌合抗原受体（α-LGR5-CAR）。 α-LGR5-ADC 是体外靶向 LGR5+ 癌细胞的最有效方式，并在人 NALM6 pre-B-ALL 小鼠模型中证明了有效的抗肿瘤功效，可将肿瘤损耗降至对照治疗的 1% 以下。 α-LGR5-BiTE 治疗在 B-ALL 前癌症模型中效果较差，但促进肿瘤负荷双倍减少。 α-LGR5-CAR-T 细胞还在体外表现出特异性和有效的 LGR5+ 癌细胞杀伤作用，并有效地靶向肿瘤，与对照相比，B-ALL 前的肿瘤负荷减少了四倍。综上所述，我们表明α-LGR5不仅可以用作研究工具和生物标志物，而且还为针对一系列表达LGR5的癌细胞的高效免疫治疗组合提供了多功能构建模块。