A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors
ErbB-2 is an orphan receptor that belongs to a family of tyrosine kinase receptors for either epidermal growth factor (EGF) or Neu differentiation factor (NDF/neuregulin). Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical course of certain human...
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| Veröffentlicht in: | Oncogene 1997-05, Vol.14 (17), p.2099-2109 |
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| creator | KLAPPER, L. N VAISMAN, N HURWITZ, E PINKAS-KRAMARSKI, R YARDEN, Y SELA, M |
| description | ErbB-2 is an orphan receptor that belongs to a family of tyrosine kinase receptors for either epidermal growth factor (EGF) or Neu differentiation factor (NDF/neuregulin). Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical course of certain human adenocarcinomas, the encoded protein is an attractive target for immunotherapy. Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 effectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely understood. To study this question, we generated a large battery of mAbs to ErbB-2, that were classified epitopically. Whereas most antibodies stimulated tyrosine phosphorylation of ErbB-2, their anti-tumor effect correlated with its accelerated endocytic degradation. One group of tumor-inhibitory mAbs (Class II mAbs) was elicited by the most antigenic site of ErbB-2, and inhibited in trans binding of NDF and EGF to their direct receptors. The inhibitory effect was due to acceleration of ligand dissociation, and it resulted in the reduction of the ability of ErbB-2 to transactivate the mitogenic signals of NDF and EGF. These results identify two potential mechanisms of antibody-induced therapy: acceleration of ErbB-2 endocytosis by homodimerization and blocking of heterodimerization between ErbB-2 and growth factor receptors. |
| doi_str_mv | 10.1038/sj.onc.1201029 |
| format | Article |
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N ; VAISMAN, N ; HURWITZ, E ; PINKAS-KRAMARSKI, R ; YARDEN, Y ; SELA, M</creator><creatorcontrib>KLAPPER, L. N ; VAISMAN, N ; HURWITZ, E ; PINKAS-KRAMARSKI, R ; YARDEN, Y ; SELA, M</creatorcontrib><description>ErbB-2 is an orphan receptor that belongs to a family of tyrosine kinase receptors for either epidermal growth factor (EGF) or Neu differentiation factor (NDF/neuregulin). Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical course of certain human adenocarcinomas, the encoded protein is an attractive target for immunotherapy. Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 effectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely understood. To study this question, we generated a large battery of mAbs to ErbB-2, that were classified epitopically. Whereas most antibodies stimulated tyrosine phosphorylation of ErbB-2, their anti-tumor effect correlated with its accelerated endocytic degradation. One group of tumor-inhibitory mAbs (Class II mAbs) was elicited by the most antigenic site of ErbB-2, and inhibited in trans binding of NDF and EGF to their direct receptors. The inhibitory effect was due to acceleration of ligand dissociation, and it resulted in the reduction of the ability of ErbB-2 to transactivate the mitogenic signals of NDF and EGF. These results identify two potential mechanisms of antibody-induced therapy: acceleration of ErbB-2 endocytosis by homodimerization and blocking of heterodimerization between ErbB-2 and growth factor receptors.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1201029</identifier><identifier>PMID: 9160890</identifier><language>eng</language><publisher>Basingstoke: Nature Publishing</publisher><subject>Animal models ; Animals ; Antibodies, Monoclonal - pharmacology ; Biological and medical sciences ; Cell cycle, cell proliferation ; Cell physiology ; Clinical trials ; Dimerization ; Endocytosis ; Endocytosis - drug effects ; Epidermal growth factor ; Epidermal Growth Factor - antagonists & inhibitors ; Epidermal Growth Factor - pharmacology ; Epitopes - immunology ; ErbB protein ; ErbB-2 protein ; Fundamental and applied biological sciences. Psychology ; Glycoproteins - antagonists & inhibitors ; Glycoproteins - pharmacology ; Growth factor receptors ; Humans ; Immunotherapy ; Kinases ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Models, Biological ; Molecular and cellular biology ; Monoclonal antibodies ; Multigene Family ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - chemistry ; Neoplasm Proteins - immunology ; Neuregulin ; Neuregulins ; Phosphorylation ; Protein-tyrosine kinase ; Receptor, ErbB-2 - antagonists & inhibitors ; Receptor, ErbB-2 - chemistry ; Receptor, ErbB-2 - immunology ; Receptors, Growth Factor - drug effects ; Signal Transduction - drug effects ; Tumors</subject><ispartof>Oncogene, 1997-05, Vol.14 (17), p.2099-2109</ispartof><rights>1997 INIST-CNRS</rights><rights>Macmillan Publishers Limited 1997.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c378t-3fbdac956583f03c8c515c341ef5f32b8af5742dedddf5036da95cc3ebfbb8c73</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2710132$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9160890$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KLAPPER, L. N</creatorcontrib><creatorcontrib>VAISMAN, N</creatorcontrib><creatorcontrib>HURWITZ, E</creatorcontrib><creatorcontrib>PINKAS-KRAMARSKI, R</creatorcontrib><creatorcontrib>YARDEN, Y</creatorcontrib><creatorcontrib>SELA, M</creatorcontrib><title>A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors</title><title>Oncogene</title><addtitle>Oncogene</addtitle><description>ErbB-2 is an orphan receptor that belongs to a family of tyrosine kinase receptors for either epidermal growth factor (EGF) or Neu differentiation factor (NDF/neuregulin). Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical course of certain human adenocarcinomas, the encoded protein is an attractive target for immunotherapy. Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 effectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely understood. To study this question, we generated a large battery of mAbs to ErbB-2, that were classified epitopically. Whereas most antibodies stimulated tyrosine phosphorylation of ErbB-2, their anti-tumor effect correlated with its accelerated endocytic degradation. One group of tumor-inhibitory mAbs (Class II mAbs) was elicited by the most antigenic site of ErbB-2, and inhibited in trans binding of NDF and EGF to their direct receptors. The inhibitory effect was due to acceleration of ligand dissociation, and it resulted in the reduction of the ability of ErbB-2 to transactivate the mitogenic signals of NDF and EGF. These results identify two potential mechanisms of antibody-induced therapy: acceleration of ErbB-2 endocytosis by homodimerization and blocking of heterodimerization between ErbB-2 and growth factor receptors.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell cycle, cell proliferation</subject><subject>Cell physiology</subject><subject>Clinical trials</subject><subject>Dimerization</subject><subject>Endocytosis</subject><subject>Endocytosis - drug effects</subject><subject>Epidermal growth factor</subject><subject>Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Epidermal Growth Factor - pharmacology</subject><subject>Epitopes - immunology</subject><subject>ErbB protein</subject><subject>ErbB-2 protein</subject><subject>Fundamental and applied biological sciences. 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N ; VAISMAN, N ; HURWITZ, E ; PINKAS-KRAMARSKI, R ; YARDEN, Y ; SELA, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-3fbdac956583f03c8c515c341ef5f32b8af5742dedddf5036da95cc3ebfbb8c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell cycle, cell proliferation</topic><topic>Cell physiology</topic><topic>Clinical trials</topic><topic>Dimerization</topic><topic>Endocytosis</topic><topic>Endocytosis - drug effects</topic><topic>Epidermal growth factor</topic><topic>Epidermal Growth Factor - antagonists & inhibitors</topic><topic>Epidermal Growth Factor - pharmacology</topic><topic>Epitopes - immunology</topic><topic>ErbB protein</topic><topic>ErbB-2 protein</topic><topic>Fundamental and applied biological sciences. 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N</au><au>VAISMAN, N</au><au>HURWITZ, E</au><au>PINKAS-KRAMARSKI, R</au><au>YARDEN, Y</au><au>SELA, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors</atitle><jtitle>Oncogene</jtitle><addtitle>Oncogene</addtitle><date>1997-05-01</date><risdate>1997</risdate><volume>14</volume><issue>17</issue><spage>2099</spage><epage>2109</epage><pages>2099-2109</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>ErbB-2 is an orphan receptor that belongs to a family of tyrosine kinase receptors for either epidermal growth factor (EGF) or Neu differentiation factor (NDF/neuregulin). Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical course of certain human adenocarcinomas, the encoded protein is an attractive target for immunotherapy. Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 effectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely understood. To study this question, we generated a large battery of mAbs to ErbB-2, that were classified epitopically. Whereas most antibodies stimulated tyrosine phosphorylation of ErbB-2, their anti-tumor effect correlated with its accelerated endocytic degradation. One group of tumor-inhibitory mAbs (Class II mAbs) was elicited by the most antigenic site of ErbB-2, and inhibited in trans binding of NDF and EGF to their direct receptors. The inhibitory effect was due to acceleration of ligand dissociation, and it resulted in the reduction of the ability of ErbB-2 to transactivate the mitogenic signals of NDF and EGF. These results identify two potential mechanisms of antibody-induced therapy: acceleration of ErbB-2 endocytosis by homodimerization and blocking of heterodimerization between ErbB-2 and growth factor receptors.</abstract><cop>Basingstoke</cop><pub>Nature Publishing</pub><pmid>9160890</pmid><doi>10.1038/sj.onc.1201029</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 1997-05, Vol.14 (17), p.2099-2109 |
| issn | 0950-9232 1476-5594 |
| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature; EZB-FREE-00999 freely available EZB journals |
| subjects | Animal models Animals Antibodies, Monoclonal - pharmacology Biological and medical sciences Cell cycle, cell proliferation Cell physiology Clinical trials Dimerization Endocytosis Endocytosis - drug effects Epidermal growth factor Epidermal Growth Factor - antagonists & inhibitors Epidermal Growth Factor - pharmacology Epitopes - immunology ErbB protein ErbB-2 protein Fundamental and applied biological sciences. Psychology Glycoproteins - antagonists & inhibitors Glycoproteins - pharmacology Growth factor receptors Humans Immunotherapy Kinases Mice Mice, Inbred BALB C Mice, Nude Models, Biological Molecular and cellular biology Monoclonal antibodies Multigene Family Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - chemistry Neoplasm Proteins - immunology Neuregulin Neuregulins Phosphorylation Protein-tyrosine kinase Receptor, ErbB-2 - antagonists & inhibitors Receptor, ErbB-2 - chemistry Receptor, ErbB-2 - immunology Receptors, Growth Factor - drug effects Signal Transduction - drug effects Tumors |
| title | A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors |
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