Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer
ANNALS OF ONCOLOGY
Authors: M-Rabet, M.; Cabaud, O.; Josselin, E.; Finetti, P.; Castellano, R.; Farina, A.; Agavnian-Couquiaud, E.; Saviane, G.; Collette, Y.; Viens, P.; Goncalves, A.; Ginestier, C.; Charafe-Jauffret, E.; Birnbaum, D.; Olive, D.; Bertucci, F.; Lopez, M.
Abstract
Background: Triple-negative breast cancers (TNBCs) are associated with a poor prognosis. In contrast to other molecular sub-types, 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 sub-types. 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.
Using the ferret model to study morbillivirus entry, spread, transmission and cross-species infection
CURRENT OPINION IN VIROLOGY
Authors: Ludlow, Martin; Rennick, Linda J.; Nambulli, Sham; de Swart, Rik L.; Duprex, W. Paul
Abstract
Canine distemper virus (CDV) is an animal morbillivirus with a worldwide circulation that infects carnivores, including domestic dogs and an assortment of wildlife hosts. The development of reverse genetics systems for wild-type strains of CDV and the use of the resulting recombinant (r) viruses to infect ferrets by a natural route has shed new light on the temporal pathogenesis of distemper. Combining fluorescent protein expressing recombinant viruses and multimodal, macroscopic and microscopic imaging modalities has highlighted the differential role of the cellular receptors CD150 and PVRL4 in disease progression. This in turn has enabled pathways of viral spread, including multiple routes of entry into the central nervous system, to be mapped with unparalleled sensitivity.