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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2022
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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) |
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ADAM17 Monoclonal antibody EGFR signaling Cancer therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
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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 |
work_keys_str_mv |
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