Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells

ADAM17 is upregulated in many cancers and in turn activates signaling pathways, including EGFR/ErbB, as well as those underlying resistance to targeted anti-EGFR therapies. Due to its central role in oncogenic pathways and drug resistance mechanisms, specific and efficacious monoclonal antibodies ag...

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Autores principales: Nayanendu Saha, Kai Xu, Zhongyu Zhu, Dorothea Robev, Teja Kalidindi, Yan Xu, Juha Himanen, Elisa de Stanchina, Naga Vara Kishore Pillarsetty, Dimiter S Dimitrov, Dimitar B Nikolov
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Publicado: Elsevier 2022
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Acceso en línea:https://doaj.org/article/0c1537a2f183403bbaf393d83c36b312
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spelling oai:doaj.org-article:0c1537a2f183403bbaf393d83c36b3122021-11-12T04:29:48ZInhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells1936-523310.1016/j.tranon.2021.101265https://doaj.org/article/0c1537a2f183403bbaf393d83c36b3122022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1936523321002564https://doaj.org/toc/1936-5233ADAM17 is upregulated in many cancers and in turn activates signaling pathways, including EGFR/ErbB, as well as those underlying resistance to targeted anti-EGFR therapies. Due to its central role in oncogenic pathways and drug resistance mechanisms, specific and efficacious monoclonal antibodies against ADAM17 could be useful for a broad patient population with solid tumors. Hence, we describe here an inhibitory anti-ADAM17 monoclonal antibody, named D8P1C1, that preferentially recognizes ADAM17 on cancer cells. D8P1C1 inhibits the catalytic activity of ADAM17 in a fluorescence-based peptide cleavage assay, as well as the proliferation of a range of cancer cell lines, including breast, ovarian, glioma, colon and the lung adenocarcinoma. In mouse models of triple-negative breast cancer and ovarian cancer, treatment with the mAb results in 78% and 45% tumor growth inhibition, respectively. Negative staining electron microscopy analysis of the ADAM17 ectodomain in complex with D8P1C1 reveals that the mAb binds the ADAM17 protease domain, consistent with its ability to inhibit the ADAM17 catalytic activity. Collectively, our results demonstrate the therapeutic potential of the D8P1C1 mAb to treat solid tumors.Nayanendu SahaKai XuZhongyu ZhuDorothea RobevTeja KalidindiYan XuJuha HimanenElisa de StanchinaNaga Vara Kishore PillarsettyDimiter S DimitrovDimitar B NikolovElsevierarticleADAM17Monoclonal antibodyEGFR signalingCancer therapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENTranslational Oncology, Vol 15, Iss 1, Pp 101265- (2022)
institution DOAJ
collection DOAJ
language EN
topic ADAM17
Monoclonal antibody
EGFR signaling
Cancer therapy
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
spellingShingle ADAM17
Monoclonal antibody
EGFR signaling
Cancer therapy
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Nayanendu Saha
Kai Xu
Zhongyu Zhu
Dorothea Robev
Teja Kalidindi
Yan Xu
Juha Himanen
Elisa de Stanchina
Naga Vara Kishore Pillarsetty
Dimiter S Dimitrov
Dimitar B Nikolov
Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells
description ADAM17 is upregulated in many cancers and in turn activates signaling pathways, including EGFR/ErbB, as well as those underlying resistance to targeted anti-EGFR therapies. Due to its central role in oncogenic pathways and drug resistance mechanisms, specific and efficacious monoclonal antibodies against ADAM17 could be useful for a broad patient population with solid tumors. Hence, we describe here an inhibitory anti-ADAM17 monoclonal antibody, named D8P1C1, that preferentially recognizes ADAM17 on cancer cells. D8P1C1 inhibits the catalytic activity of ADAM17 in a fluorescence-based peptide cleavage assay, as well as the proliferation of a range of cancer cell lines, including breast, ovarian, glioma, colon and the lung adenocarcinoma. In mouse models of triple-negative breast cancer and ovarian cancer, treatment with the mAb results in 78% and 45% tumor growth inhibition, respectively. Negative staining electron microscopy analysis of the ADAM17 ectodomain in complex with D8P1C1 reveals that the mAb binds the ADAM17 protease domain, consistent with its ability to inhibit the ADAM17 catalytic activity. Collectively, our results demonstrate the therapeutic potential of the D8P1C1 mAb to treat solid tumors.
format article
author Nayanendu Saha
Kai Xu
Zhongyu Zhu
Dorothea Robev
Teja Kalidindi
Yan Xu
Juha Himanen
Elisa de Stanchina
Naga Vara Kishore Pillarsetty
Dimiter S Dimitrov
Dimitar B Nikolov
author_facet Nayanendu Saha
Kai Xu
Zhongyu Zhu
Dorothea Robev
Teja Kalidindi
Yan Xu
Juha Himanen
Elisa de Stanchina
Naga Vara Kishore Pillarsetty
Dimiter S Dimitrov
Dimitar B Nikolov
author_sort Nayanendu Saha
title Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells
title_short Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells
title_full Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells
title_fullStr Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells
title_full_unstemmed Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells
title_sort inhibitory monoclonal antibody targeting adam17 expressed on cancer cells
publisher Elsevier
publishDate 2022
url https://doaj.org/article/0c1537a2f183403bbaf393d83c36b312
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