Disease progression and treatment resistance in colorectal and other cancers are driven by a subset of cells within the tumor that have stem-cell-like properties and long-term tumorigenic potential. These stem-cell-like cells express the leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) and have characteristics similar to tissue-resident stem cells in normal adult tissues such as the colon. Organoid models of murine and human colorectal and other cancers contain LGR5-expressing (LGR5+) stem-cell-like cells and can be used to investigate the underlying mechanisms of cancer development, progression, therapy vulnerability, and resistance. A large biobank of organoids derived from colorectal cancer or adjacent normal tissue was developed. We performed a large-scale unbiased functional screen to identify bispecific antibodies (BsAbs) that preferentially inhibit the growth of colon tumor-derived, as compared to normal tissue-derived, organoids. We identified the most potent BsAb in the screen as petosemtamab, a Biclonics®BsAb targeting both LGR5 and the epidermal growth factor receptor (EGFR). Petosemtamab employs three distinct mechanisms of action: EGFR ligand blocking, EGFR receptor internalization and degradation in LGR5+ cells, and Fc-mediated activation of the innate immune system by antibody-dependent cellular phagocytosis (ADCP) and enhanced antibody-dependent cellular cytotoxicity (ADCC) (see graphical abstract). Petosemtamab has demonstrated substantial clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). The safety profile is generally favorable, with low rates of skin and gastrointestinal toxicity. Phase 3 trials are ongoing in both first-line programmed death-ligand 1-positive (PD-L1+) and second/third-line r/m HNSCC.
结直肠癌及其他癌症的疾病进展和治疗耐药性是由肿瘤内具有干细胞样特性及长期致瘤潜能的细胞亚群所驱动。这些干细胞样细胞表达富含亮氨酸重复序列的G蛋白偶联受体5（LGR5），其特性与正常成人组织（如结肠）中的组织驻留干细胞相似。小鼠和人类结直肠癌及其他癌症的类器官模型均含有LGR5阳性（LGR5+）干细胞样细胞，可用于研究癌症发生、进展、治疗敏感性和耐药性的潜在机制。本研究建立了源自结直肠癌及癌旁正常组织的大型类器官生物样本库。通过大规模无偏倚功能筛选，我们鉴定出能优先抑制结肠肿瘤来源类器官生长（相较于正常组织来源类器官）的双特异性抗体（BsAbs）。筛选中最有效的双特异性抗体被确定为petosemtamab，这是一种靶向LGR5与表皮生长因子受体（EGFR）的Biclonics®双特异性抗体。Petosemtamab通过三种独特机制发挥作用：阻断EGFR配体、促进LGR5+细胞中EGFR受体内吞与降解，以及通过抗体依赖性细胞吞噬作用（ADCP）和增强的抗体依赖性细胞毒性（ADCC）介导Fc段激活先天免疫系统（参见图示摘要）。Petosemtamab在复发性/转移性头颈部鳞状细胞癌（r/m HNSCC）中已显示出显著的临床活性，其安全性总体良好，皮肤及胃肠道毒性发生率较低。目前正在一线程序性死亡配体1阳性（PD-L1+）及二线/三线r/m HNSCC患者中开展III期临床试验。
肿瘤(癌症)患者之家