M M-Rabet1, O Cabaud2, E Josselin3, P Finetti4, R Castellano5, A Farina6, E Agavnian-Couquiaud6, G Saviane4, Y Collette5, P Viens7, A Gonçalves7, C Ginestier4, E Charafe-Jauffret4, D Birnbaum4, D Olive1, F Bertucci4,7, M Lopez4. 1. Centre de Cancérologie de Marseille, INSERM U1068, Equipe Immunité et Cancer, Institut Paoli-Calmettes, Aix-Marseille Université, CNRS, UMR7258, Marseille, France. 2. Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France. 3. CRCM, INSERM, U1068; Institut Paoli-Calmettes; Aix-Marseille Université; CNRS, UMR 7258, Marseille, France. 4. Aix Marseille Université, CNRS, INSERM , Institut Paoli-Calmettes, CRCM, Equipe Oncologie Moléculaire labellisée 'Ligue contre le cancer' , Marseille , France. 5. TrGET Platform, Inserm, U1068, Marseille F-13009, France. 6. ICEP Platform, Inserm, U1068, CRCM, Institut Paoli Calmettes, Aix-Marseille Université, UM 105, CNRS, UMR7258. 7. Département d'Oncologie Médicale, Institut Paoli Calmettes, Aix-Marseille Université, UM 105, Marseille, France.
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.
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-4tumour 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.