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A novel inhibitory anti-invasive MAb isolated using phenotypic screening highlights AnxA6 as a functionally relevant target protein in pancreatic cancer
O'Sullivan, Dermot; Dowling, Paul; Joyce, Helena; McAuley, Edel; McCann, Andrew; Henry, Michael; McGovern, Brianan; Barham, Paul; Kelleher, Fergal C.; Murphy, Jean; Kennedy, Susan; Swan, Niall; Moriarty, Michael; Clynes, Martin; Larkin, Annemarie
Background: Discovery and validation of new antibody tractable targets is critical for the development of new antibody therapeutics to address unmet needs in oncology. Methods: A highly invasive clonal variant of the MDA-MB-435S cell line was used to generate monoclonal antibodies (MAbs), which were screened for anti-invasive activity against aggressive cancer cells in vitro. The molecular target of selected inhibitory MAb 9E1 was identified using immunoprecipitation/liquid chromatography-tandem mass spectrometry. The potential anti-tumour effects of MAb 9E1 were investigated in vitro together with immunohistochemical analysis of the 9E1 target antigen in normal and cancer tissues. Results: MAb 9E1 significantly decreases invasion in pancreatic, lung squamous and breast cancer cells and silencing of its target antigen, which was revealed as AnxA6, leads to markedly reduced invasive capacity of pancreatic and lung squamous cancer in vitro. IHC using MAb 9E1 revealed that AnxA6 exhibits a high prevalence of membrane immunoreactivity across aggressive tumour types with restricted expression observed in the majority of normal tissues. In pancreatic ductal adenocarcinoma, high AnxA6 IHC score correlated with the presence of tumour budding at the invasive front of tumours (P=0.082), the presence of perineural invasion (P= <0.0001) and showed a weak correlation with reduced survival (P=0.2242). Conclusions: This study highlights the use of phenotypic hybridoma screening as an effective strategy to select a novel function-blocking MAb, 9E1 with anti-cancer activity in vitro. Moreover, through characterisation of the 9E1 target antigen, AnxA6, our findings support further investigation of AnxA6 as a potential candidate target for antibody-mediated inhibition of pancreatic cancer.
Keyword(s): monoclonal antibody; cancer invasion; novel target; therapeutic antibody; annexin A6; pancreatic adenocarcinoma
Publication Date:
Type: Journal article
Peer-Reviewed: Yes
Institution: Maynooth University
Citation(s): O'Sullivan, Dermot and Dowling, Paul and Joyce, Helena and McAuley, Edel and McCann, Andrew and Henry, Michael and McGovern, Brianan and Barham, Paul and Kelleher, Fergal C. and Murphy, Jean and Kennedy, Susan and Swan, Niall and Moriarty, Michael and Clynes, Martin and Larkin, Annemarie (2017) A novel inhibitory anti-invasive MAb isolated using phenotypic screening highlights AnxA6 as a functionally relevant target protein in pancreatic cancer. British Journal of Cancer, 117 (9). pp. 1326-1335. ISSN 1532-1827
Publisher(s): Cancer Research UK
File Format(s): other
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First Indexed: 2020-04-02 06:07:29 Last Updated: 2020-04-02 06:07:29