浙江大学姚航平团队发现，人源化的双靶向抗体–药物偶联物特异性靶向MET和RON受体，可作为治疗表现出表型异质性的癌症的药物策略。该项研究成果于2025年1月21日在线发表在《中国药理学报》上。

研究人员表示，癌症异质性特征表现为肿瘤细胞群体的多样性，其中包括受体酪氨酸激酶的不同表型和表达。间充质–上皮过渡（MET）和recepteur d’origine nantais（RON）受体的异常表达促进了癌细胞的表型异质性，这对治疗构成了重大挑战。

研究人员旨在开发一种双靶向抗体–药物偶联物（ADC），能够同时作用于MET和RON，以治疗具有高表型异质性的癌症。通过免疫组织化学染色，研究人员发现MET和RON的表达具有高度异质性，在40%以上的胰腺癌和三阴性乳腺癌病例中表现出不同的组合。此种表达异质性为同时靶向这两种受体提供了治疗依据。通过单克隆抗体序列的IgG重组，研究人员生成了一种人源化双特异性单克隆抗体（PCMbs–MR），特异性靶向MET和RON。

将单甲基奥瑞斯塔汀E与PCMbs–MR偶联，研究人员生成了双靶向ADC（PCMdt–MMAE），其药物–抗体比为4:1。研究人员使用了不同的癌细胞系评估PCMdt–MMAE的生物学活性，并在多个异种移植肿瘤模型中评估其体内疗效。PCMdt–MMAE表现出良好的药代动力学特征，最大耐受剂量约为30 mg/kg。使用斯普拉格–道利大鼠进行的毒理学研究显示，PCMdt–MMAE相对安全，仅出现轻度至中度、暂时性和可逆的副作用。

功能研究表明，PCMdt-MMAE能显著促进MET和RON的内吞作用，并在表现出MET和RON异质性共表达的癌细胞系中引发大规模细胞死亡。体外和体内研究均表明，以ADC形式的双靶向治疗在针对MET/RON异质性表型的肿瘤中具有高度有效性和持久效果。

因此，研究人员认为双靶向ADC（靶向MET和RON）可以作为治疗表型异质性肿瘤的新型策略。

附：英文原文

Title: Humanized dual-targeting antibody–drug conjugates specific to MET and RON receptors as a pharmaceutical strategy for the treatment of cancers exhibiting phenotypic heterogeneity

Author: Wang, Minghai, Ma, Qi, Suthe, Sreedhar Reddy, Hudson, Rachel E., Pan, Jing-ying, Mikelis, Constantinos, Zhu, Miao-jin, Wu, Zhi-gang, Shi, Dan-rong, Yao, Hang-ping

Issue&Volume: 2025-01-21

Abstract: Cancer heterogeneity, characterized by diverse populations of tumorigenic cells, involves the occurrence of differential phenotypes with variable expressions of receptor tyrosine kinases. Aberrant expressions of mesenchymal–epithelial transition (MET) and recepteur d’origine nantais (RON) receptors contribute to the phenotypic heterogeneity of cancer cells, which poses a major therapeutic challenge. This study aims to develop a dual-targeting antibody–drug conjugate (ADC) that can act against both MET and RON for treating cancers with high phenotypic heterogeneity. Through immunohistochemical staining, we show that MET and RON expressions are highly heterogeneous with differential combinations in more than 40% of pancreatic and triple-negative breast cancer cases. This expressional heterogeneity provides the rationale to target both receptors for cancer therapy. A humanized bispecific monoclonal antibody specific to both MET and RON (PCMbs–MR) is generated through IgG recombination using monoclonal antibody sequences specific to MET and RON, respectively. Monomethyl auristatin E is conjugated to PCMbs–MR to generate a dual-targeting ADC (PCMdt–MMAE), with a drug-to-antibody ratio of 4:1. Various cancer cell lines were used to determine PCMdt-MMAE-mediated biological activities. The efficacy of PCMdt–MMAE in vivo is evaluated using multiple xenograft tumor models. PCMdt–MMAE shows a favorable pharmacokinetic profile, with a maximum tolerated dose of ~30mg/kg in mice. Toxicological studies using Sprague–Dawley rats reveal that PCMdt–MMAE is relatively safe with slight-to-moderate, temporary, and reversible adverse events. Functionally, PCMdt-MMAE induces a robust internalization of both MET and RON and causes a large-scale cell death in cancer cell lines exhibiting MET and RON heterogeneous co-expressions. Both in vitro and in vivo studies demonstrate that the dual-targeting approach in the form of an ADC is highly effective with a long-lasting effect against tumors exhibiting MET/RON heterogeneous phenotypes. Hence, we can suggest that a dual-targeting ADC specific to both MET and RON can be employed as a novel therapeutic strategy for tumors with expressional phenotypic heterogeneity.

DOI: 10.1038/s41401-024-01458-7

Source: https://www.nature.com/articles/s41401-024-01458-7