Nectin-4：一种新型预后生物标志物，可有效靶向治疗原发性和转移性三阴性乳腺癌。

Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer.

机构信息

Centre de Cancérologie de Marseille, INSERM U1068, Equipe Immunité et Cancer, Institut Paoli-Calmettes, Aix-Marseille Université, CNRS, UMR7258, Marseille, France.

Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.

出版信息

Ann Oncol. 2017 Apr 1;28(4):769-776. doi: 10.1093/annonc/mdw678.

DOI:10.1093/annonc/mdw678

PMID:27998973

Abstract

BACKGROUND

Triple-negative breast cancers (TNBCs) are associated with a poor prognosis. In contrast to other molecular subtypes, they have no identified specific target and chemotherapy remains the only available systemic treatment. The adhesion molecule nectin-4 represents a new potential therapeutic target in different cancer models. Here, we have tested the prognostic value of nectin-4 expression and assessed the therapeutic efficiency of an anti-nectin 4 antibody drug conjugate (ADC) on localised and metastatic TNBC in vitro and in vivo.

MATERIALS AND METHODS

We analysed nectin-4/PVRL4 mRNA expression in 5673 invasive breast cancers and searched for correlations with clinicopathological features including metastasis-free survival (MFS). Immunohistochemistry was carried out in 61 TNBCs and in samples of primary TNBC Patient-Derived Xenografts (PDXs). An anti-nectin-4 antibody eligible for ADC was produced and tested in vitro and in vivo in localised and metastatic TNBC PDXs.

RESULTS

High nectin-4/PVRL4 mRNA expression was associated with poor-prognosis features including the TN and basal subtypes. High PVRL4 mRNA expression showed independent negative prognostic value for MFS in multivariate analysis in TNBCs. Nectin-4 protein expression was not detected in adult healthy tissues including mammary tissue. Membranous protein expression was found in 62% of TNBCs, with strong correlation with mRNA expression. We developed an ADC (N41mab-vcMMAE) comprising a human anti-nectin-4 monoclonal antibody conjugated to monomethyl auristatin-E (MMAE). In vitro, this ADC bound to nectin-4 with high affinity and specificity and induced its internalisation as well as dose-dependent cytotoxicity on nectin-4-expressing breast cancer cell lines. In vivo, this ADC induced rapid, complete and durable responses on nectin-4-positive xenograft TNBC samples including primary tumours, metastatic lesions, and local relapses; efficiency was dependent on both the dose and the nectin-4 tumour expression level.

CONCLUSION

Nectin-4 is both a new promising prognostic biomarker and specific therapeutic target for ADC in the very limited armamentarium against TNBC.

摘要

背景

三阴性乳腺癌（TNBC）预后较差。与其他分子亚型相比，它没有明确的特定靶点，化疗仍然是唯一可用的全身治疗方法。黏附分子 nectin-4 代表了不同癌症模型中的一个新的潜在治疗靶点。在这里，我们检测了 nectin-4 表达的预后价值，并评估了针对局部和转移性 TNBC 的抗 nectin-4 抗体药物偶联物（ADC）的治疗效果。

材料和方法

我们分析了 5673 例浸润性乳腺癌中 nectin-4/PVRL4 mRNA 的表达，并寻找与临床病理特征的相关性，包括无转移生存率（MFS）。在 61 例 TNBC 病例和原发性 TNBC 患者来源异种移植（PDX）样本中进行了免疫组化检测。生产了一种适用于 ADC 的抗 nectin-4 抗体，并在局部和转移性 TNBC PDX 中进行了体外和体内研究。

结果

高 nectin-4/PVRL4 mRNA 表达与预后不良特征相关，包括 TN 和基底亚型。在多变量分析中，高 PVRL4 mRNA 表达对 TNBC 的 MFS 具有独立的负预后价值。在成人健康组织中，包括乳腺组织中均未检测到 nectin-4 蛋白表达。在 62%的 TNBC 中发现了膜蛋白表达，与 mRNA 表达具有很强的相关性。我们开发了一种 ADC（N41mab-vcMMAE），由与人 nectin-4 单克隆抗体连接的单甲基澳瑞他汀 E（MMAE）组成。在体外，该 ADC 以高亲和力和特异性与 nectin-4 结合，并诱导其内化以及对 nectin-4 表达的乳腺癌细胞系的剂量依赖性细胞毒性。在体内，该 ADC 对 nectin-4 阳性的异种移植 TNBC 样本，包括原发肿瘤、转移病灶和局部复发，迅速、完全和持久地产生反应；效率取决于剂量和 nectin-4 肿瘤表达水平。