A potent anti-HB-EGF monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of HB-EGF.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family and has a variety of physiological and pathological functions. Modulation of HB-EGF activity might have a therapeutic potential in the oncology area. We explored the therapeutic poss...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3522611?pdf=render |
| _version_ | 1818176178318475264 |
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| author | Shuji Sato Andrew W Drake Isamu Tsuji Jinhong Fan |
| author_facet | Shuji Sato Andrew W Drake Isamu Tsuji Jinhong Fan |
| author_sort | Shuji Sato |
| collection | DOAJ |
| description | Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family and has a variety of physiological and pathological functions. Modulation of HB-EGF activity might have a therapeutic potential in the oncology area. We explored the therapeutic possibilities by characterizing the in vitro biological activity of anti-HB-EGF monoclonal antibody Y-142. EGF receptor (EGFR) ligand and species specificities of Y-142 were tested. Neutralizing activities of Y-142 against HB-EGF were evaluated in EGFR and ERBB4 signaling. Biological activities of Y-142 were assessed in cancer cell proliferation and angiogenesis assays and compared with the anti-EGFR antibody cetuximab, the HB-EGF inhibitor CRM197, and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. The binding epitope was determined with alanine scanning. Y-142 recognized HB-EGF as well as the EGFR ligand amphiregulin, and bound specifically to human HB-EGF, but not to rodent HB-EGF. In addition, Y-142 neutralized HB-EGF-induced phosphorylation of EGFR and ERBB4, and blocked their downstream ERK1/2 and AKT signaling. We also found that Y-142 inhibited HB-EGF-induced cancer cell proliferation, endothelial cell proliferation, tube formation, and VEGF production more effectively than cetuximab and CRM197 and that Y-142 was superior to bevacizumab in the inhibition of HB-EGF-induced tube formation. Six amino acids in the EGF-like domain were identified as the Y-142 binding epitope. Among the six amino acids, the combination of F115 and Y123 determined the amphiregulin cross-reactivity and that F115 accounted for the species selectivity. Furthermore, it was suggested that the potent neutralizing activity of Y-142 was derived from its recognition of R142 and Y123 and its high affinity to HB-EGF. Y-142 has a potent HB-EGF neutralizing activity that modulates multiple biological activities of HB-EGF including cancer cell proliferation and angiogenic activities. Y-142 may have a potential to be developed into a therapeutic agent for the treatment of HB-EGF-dependent cancers. |
| first_indexed | 2024-12-11T20:12:03Z |
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| id | doaj.art-c6b8267b4c4640fba1db816f1a6c3ba5 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T20:12:03Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c6b8267b4c4640fba1db816f1a6c3ba52022-12-22T00:52:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01712e5196410.1371/journal.pone.0051964A potent anti-HB-EGF monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of HB-EGF.Shuji SatoAndrew W DrakeIsamu TsujiJinhong FanHeparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family and has a variety of physiological and pathological functions. Modulation of HB-EGF activity might have a therapeutic potential in the oncology area. We explored the therapeutic possibilities by characterizing the in vitro biological activity of anti-HB-EGF monoclonal antibody Y-142. EGF receptor (EGFR) ligand and species specificities of Y-142 were tested. Neutralizing activities of Y-142 against HB-EGF were evaluated in EGFR and ERBB4 signaling. Biological activities of Y-142 were assessed in cancer cell proliferation and angiogenesis assays and compared with the anti-EGFR antibody cetuximab, the HB-EGF inhibitor CRM197, and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. The binding epitope was determined with alanine scanning. Y-142 recognized HB-EGF as well as the EGFR ligand amphiregulin, and bound specifically to human HB-EGF, but not to rodent HB-EGF. In addition, Y-142 neutralized HB-EGF-induced phosphorylation of EGFR and ERBB4, and blocked their downstream ERK1/2 and AKT signaling. We also found that Y-142 inhibited HB-EGF-induced cancer cell proliferation, endothelial cell proliferation, tube formation, and VEGF production more effectively than cetuximab and CRM197 and that Y-142 was superior to bevacizumab in the inhibition of HB-EGF-induced tube formation. Six amino acids in the EGF-like domain were identified as the Y-142 binding epitope. Among the six amino acids, the combination of F115 and Y123 determined the amphiregulin cross-reactivity and that F115 accounted for the species selectivity. Furthermore, it was suggested that the potent neutralizing activity of Y-142 was derived from its recognition of R142 and Y123 and its high affinity to HB-EGF. Y-142 has a potent HB-EGF neutralizing activity that modulates multiple biological activities of HB-EGF including cancer cell proliferation and angiogenic activities. Y-142 may have a potential to be developed into a therapeutic agent for the treatment of HB-EGF-dependent cancers.http://europepmc.org/articles/PMC3522611?pdf=render |
| spellingShingle | Shuji Sato Andrew W Drake Isamu Tsuji Jinhong Fan A potent anti-HB-EGF monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of HB-EGF. PLoS ONE |
| title | A potent anti-HB-EGF monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of HB-EGF. |
| title_full | A potent anti-HB-EGF monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of HB-EGF. |
| title_fullStr | A potent anti-HB-EGF monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of HB-EGF. |
| title_full_unstemmed | A potent anti-HB-EGF monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of HB-EGF. |
| title_short | A potent anti-HB-EGF monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of HB-EGF. |
| title_sort | potent anti hb egf monoclonal antibody inhibits cancer cell proliferation and multiple angiogenic activities of hb egf |
| url | http://europepmc.org/articles/PMC3522611?pdf=render |
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