Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk
The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistanc...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2015-01, Vol.75 (1), p.159-170 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | Hu, Shi Fu, Wenyan Xu, Weihao Yang, Yang Cruz, Melissa Berezov, Sandra D Jorissen, Daniel Takeda, Hiroaki Zhu, Wangdong |
| description | The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti-HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody. |
| doi_str_mv | 10.1158/0008-5472.can-14-1670 |
| format | Article |
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However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti-HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-14-1670</identifier><identifier>PMID: 25371409</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal, Humanized - pharmacology ; Bevacizumab ; Cell Growth Processes - drug effects ; Cell Growth Processes - immunology ; Cell Line, Tumor ; ErbB Receptors - antagonists & inhibitors ; ErbB Receptors - immunology ; ErbB Receptors - metabolism ; Female ; Humans ; Immunoglobulin G - immunology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mice, SCID ; Neoplasms - immunology ; Neoplasms - therapy ; Proto-Oncogene Proteins c-met - metabolism ; Random Allocation ; Receptor Cross-Talk - drug effects ; Receptor, ErbB-2 - antagonists & inhibitors ; Receptor, ErbB-2 - immunology ; Receptor, ErbB-2 - metabolism ; Receptor, ErbB-3 - antagonists & inhibitors ; Receptor, ErbB-3 - immunology ; Receptor, ErbB-3 - metabolism ; Signal Transduction ; Trastuzumab ; Vascular Endothelial Growth Factor A - antagonists & inhibitors ; Vascular Endothelial Growth Factor A - immunology ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>Cancer research (Chicago, Ill.), 2015-01, Vol.75 (1), p.159-170</ispartof><rights>2014 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-c06f08d10680c9be9b3cb164c9d1b65d026bd4c3ad1724d8d26be28569a404a13</citedby><cites>FETCH-LOGICAL-c422t-c06f08d10680c9be9b3cb164c9d1b65d026bd4c3ad1724d8d26be28569a404a13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25371409$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Shi</creatorcontrib><creatorcontrib>Fu, Wenyan</creatorcontrib><creatorcontrib>Xu, Weihao</creatorcontrib><creatorcontrib>Yang, Yang</creatorcontrib><creatorcontrib>Cruz, Melissa</creatorcontrib><creatorcontrib>Berezov, Sandra D</creatorcontrib><creatorcontrib>Jorissen, Daniel</creatorcontrib><creatorcontrib>Takeda, Hiroaki</creatorcontrib><creatorcontrib>Zhu, Wangdong</creatorcontrib><title>Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. 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Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody.</description><subject>Animals</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Bevacizumab</subject><subject>Cell Growth Processes - drug effects</subject><subject>Cell Growth Processes - immunology</subject><subject>Cell Line, Tumor</subject><subject>ErbB Receptors - antagonists & inhibitors</subject><subject>ErbB Receptors - immunology</subject><subject>ErbB Receptors - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Immunoglobulin G - immunology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Mice, SCID</subject><subject>Neoplasms - immunology</subject><subject>Neoplasms - therapy</subject><subject>Proto-Oncogene Proteins c-met - metabolism</subject><subject>Random Allocation</subject><subject>Receptor Cross-Talk - drug effects</subject><subject>Receptor, ErbB-2 - antagonists & inhibitors</subject><subject>Receptor, ErbB-2 - immunology</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>Receptor, ErbB-3 - antagonists & inhibitors</subject><subject>Receptor, ErbB-3 - immunology</subject><subject>Receptor, ErbB-3 - metabolism</subject><subject>Signal Transduction</subject><subject>Trastuzumab</subject><subject>Vascular Endothelial Growth Factor A - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor A - immunology</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9UUlOAzEQtBCIhOUJIB854OCesWc5oigLEouEgKvlsZ3EkIyD7UHKF3g1HrZLb6qualUjdAZ0BMCrK0ppRTgrs5GSLQFGoCjpHhoCzytSMsb30fAfM0BHIbymlgPlh2iQ8bwERush-py6zhPbEtcaLNtoG6etCXglPwwO3dZ46zxOEsp4bNuVbWx0foelivbDxlQspW1DxJPZ9PESzyeP2XfMLxObxi9pjOPKu265wtoG322jdS12ix50dTd5wsq7EKJcv52gg4VcB3P6m4_R83TyNJ6T24fZzfj6liiWZZEoWixopYEWFVV1Y-omVw0UTNUamoJrmhWNZiqXGsqM6Uqn3mQVL2rJKJOQH6OLH96td--dCVFsbFBmvZatcV0QiSsHxqCmCcp_oN9HerMQW2830u8EUNG_QfQWi95iMb6-F8BE_4a0d_4r0TUbo_-3_nzPvwAQmYLr</recordid><startdate>20150101</startdate><enddate>20150101</enddate><creator>Hu, Shi</creator><creator>Fu, Wenyan</creator><creator>Xu, Weihao</creator><creator>Yang, Yang</creator><creator>Cruz, Melissa</creator><creator>Berezov, Sandra D</creator><creator>Jorissen, Daniel</creator><creator>Takeda, Hiroaki</creator><creator>Zhu, Wangdong</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150101</creationdate><title>Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk</title><author>Hu, Shi ; Fu, Wenyan ; Xu, Weihao ; Yang, Yang ; Cruz, Melissa ; Berezov, Sandra D ; Jorissen, Daniel ; Takeda, Hiroaki ; Zhu, Wangdong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-c06f08d10680c9be9b3cb164c9d1b65d026bd4c3ad1724d8d26be28569a404a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antibodies, Monoclonal, Humanized - pharmacology</topic><topic>Bevacizumab</topic><topic>Cell Growth Processes - drug effects</topic><topic>Cell Growth Processes - immunology</topic><topic>Cell Line, Tumor</topic><topic>ErbB Receptors - antagonists & inhibitors</topic><topic>ErbB Receptors - immunology</topic><topic>ErbB Receptors - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Immunoglobulin G - immunology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Mice, SCID</topic><topic>Neoplasms - immunology</topic><topic>Neoplasms - therapy</topic><topic>Proto-Oncogene Proteins c-met - metabolism</topic><topic>Random Allocation</topic><topic>Receptor Cross-Talk - drug effects</topic><topic>Receptor, ErbB-2 - antagonists & inhibitors</topic><topic>Receptor, ErbB-2 - immunology</topic><topic>Receptor, ErbB-2 - metabolism</topic><topic>Receptor, ErbB-3 - antagonists & inhibitors</topic><topic>Receptor, ErbB-3 - immunology</topic><topic>Receptor, ErbB-3 - metabolism</topic><topic>Signal Transduction</topic><topic>Trastuzumab</topic><topic>Vascular Endothelial Growth Factor A - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor A - immunology</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hu, Shi</creatorcontrib><creatorcontrib>Fu, Wenyan</creatorcontrib><creatorcontrib>Xu, Weihao</creatorcontrib><creatorcontrib>Yang, Yang</creatorcontrib><creatorcontrib>Cruz, Melissa</creatorcontrib><creatorcontrib>Berezov, Sandra D</creatorcontrib><creatorcontrib>Jorissen, Daniel</creatorcontrib><creatorcontrib>Takeda, Hiroaki</creatorcontrib><creatorcontrib>Zhu, Wangdong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hu, Shi</au><au>Fu, Wenyan</au><au>Xu, Weihao</au><au>Yang, Yang</au><au>Cruz, Melissa</au><au>Berezov, Sandra D</au><au>Jorissen, Daniel</au><au>Takeda, Hiroaki</au><au>Zhu, Wangdong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2015-01-01</date><risdate>2015</risdate><volume>75</volume><issue>1</issue><spage>159</spage><epage>170</epage><pages>159-170</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti-HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. 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| ispartof | Cancer research (Chicago, Ill.), 2015-01, Vol.75 (1), p.159-170 |
| issn | 0008-5472 1538-7445 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal, Humanized - pharmacology Bevacizumab Cell Growth Processes - drug effects Cell Growth Processes - immunology Cell Line, Tumor ErbB Receptors - antagonists & inhibitors ErbB Receptors - immunology ErbB Receptors - metabolism Female Humans Immunoglobulin G - immunology Mice Mice, Inbred BALB C Mice, Nude Mice, SCID Neoplasms - immunology Neoplasms - therapy Proto-Oncogene Proteins c-met - metabolism Random Allocation Receptor Cross-Talk - drug effects Receptor, ErbB-2 - antagonists & inhibitors Receptor, ErbB-2 - immunology Receptor, ErbB-2 - metabolism Receptor, ErbB-3 - antagonists & inhibitors Receptor, ErbB-3 - immunology Receptor, ErbB-3 - metabolism Signal Transduction Trastuzumab Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor A - immunology Vascular Endothelial Growth Factor A - metabolism |
| title | Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk |
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