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Anti-tumor effects of a 'human & mouse cross-reactive' anti-ADAM17 antibody in a pancreatic cancer model in vivo
Ye, Jie1; Yuen, Shun Ming2; Murphy, Gillian3; Xie, Ruiyu1; Kwok, Hang Fai1,2
2017-12-15
Conference Name5th Meeting of the International-Association-of-Physical-Chemists (IAPC)
Source PublicationEUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Volume110
Pages62-69
Conference DateAUG 23-26, 2016
Conference PlaceZhuhai, PEOPLES R CHINA
Publication PlacePO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
PublisherELSEVIER SCIENCE BV
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumor amongst all human cancers due to late diagnosis and resistant to treatment with chemotherapy and radiation. Preclinical and clinical studies have revealed that ErbB family for example epidermal growth factor receptor (EGFR) is a validated molecular target for pancreatic cancer prevention and therapy. The ErbB signaling cascade is regulated by a member of the ADAM (a disintegrin and metalloprotease) family, namely ADAM17, by enzymatic cleavage of precursor ligands into soluble cytokines and growth factors. Mouse genetic studies have demonstrated that ADAM17 is required for PDAC development. In this study, we evaluated the anti-tumor effects of A9(B8) IgG-the first specific ` human and mouse cross-reactive' ADAM17 inhibitory antibody on pancreatic malignant transformation. We found that inhibition of ADAM17 with A9(B8) IgG efficiently suppressed the shedding of ADAM17 substrates both in vivo and in vitro. Furthermore, we demonstrated that administration of A9(B8) IgG significantly suppressed motility in human pancreatic cancer cells and also significantly delayed tumorigenesis in the Pdx1Cre; KrasG12D; Trp53fl/+ PDAC mouse model. Inhibition of ADAM17 with A9(B8) IgG particularly affected the progression of pre-invasive pancreatic lesions to advanced PDAC in mice. Taken together, the preclinical data presented here will provide a starting point for clinical applications of ADAM17 targeted therapy.

KeywordPancreatic Ductal Adenocarcinoma (Pdac) Adam17 Inhibitory Antibody Tumorigenesis Targeted Therapy
DOI10.1016/j.ejps.2017.05.057
URLView the original
Indexed BySCI ; CPCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000414696100008
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Cited Times [WOS]:6   [WOS Record]     [Related Records in WOS]
Document TypeConference paper
CollectionFaculty of Health Sciences
Affiliation1.Univ Macau, Fac Hlth Sci, Ave Univ, Taipa, Macau, Peoples R China;
2.Univ Macau, Fac Hlth Sci, Histopathol Core, Ave Univ, Taipa, Macau, Peoples R China;
3.Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England
First Author AffilicationUniversity of Macau
Recommended Citation
GB/T 7714
Ye, Jie,Yuen, Shun Ming,Murphy, Gillian,et al. Anti-tumor effects of a 'human & mouse cross-reactive' anti-ADAM17 antibody in a pancreatic cancer model in vivo[C]. PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS:ELSEVIER SCIENCE BV,2017:62-69.
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