The 4C5 cell-impermeable anti-HSP90 antibody with anti-cancer activity, is composed of a single light chain dimer
MAb 4C5 is a cell impermeable, anti-HSP90 murine monoclonal antibody, originally produced using hybridoma technology. We have previously shown that mAb 4C5 specifically recognizes both the α- and to a lesser extent the β-isoform of HSP90. Additionally, in vitro and in vivo studies revealed that by s...
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description | MAb 4C5 is a cell impermeable, anti-HSP90 murine monoclonal antibody, originally produced using hybridoma technology. We have previously shown that mAb 4C5 specifically recognizes both the α- and to a lesser extent the β-isoform of HSP90. Additionally, in vitro and in vivo studies revealed that by selectively inhibiting the function of cell-surface HSP90, mAb 4C5 significantly impairs cancer cell invasion and metastasis. Here we describe the reconstitution of mAb 4C5 into a mouse-human chimera. More importantly we report that mAb 4C5 and consequently its chimeric counterpart are completely devoid of heavy chain and consist only of a functional kappa light chain dimer. The chimeric antibody is shown to retain the original antibody's specificity and functional properties. Thus it is capable of inhibiting the function of surface HSP90, leading to reduced cancer cell invasion in vitro. Finally, we present in vivo evidence showing that the chimeric 4C5 significantly inhibits the metastatic deposit formation of MDA-MB-453 cells into the lungs of SCID mice. These data suggest that a chimeric kappa light chain antibody could be potentially used as an anti-cancer agent, thereby introducing a novel type of antibody fragment, with reduced possible adverse immunogenic effects, into cancer therapeutics. |
doi_str_mv | 10.1371/journal.pone.0023906 |
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We have previously shown that mAb 4C5 specifically recognizes both the α- and to a lesser extent the β-isoform of HSP90. Additionally, in vitro and in vivo studies revealed that by selectively inhibiting the function of cell-surface HSP90, mAb 4C5 significantly impairs cancer cell invasion and metastasis. Here we describe the reconstitution of mAb 4C5 into a mouse-human chimera. More importantly we report that mAb 4C5 and consequently its chimeric counterpart are completely devoid of heavy chain and consist only of a functional kappa light chain dimer. The chimeric antibody is shown to retain the original antibody's specificity and functional properties. Thus it is capable of inhibiting the function of surface HSP90, leading to reduced cancer cell invasion in vitro. Finally, we present in vivo evidence showing that the chimeric 4C5 significantly inhibits the metastatic deposit formation of MDA-MB-453 cells into the lungs of SCID mice. These data suggest that a chimeric kappa light chain antibody could be potentially used as an anti-cancer agent, thereby introducing a novel type of antibody fragment, with reduced possible adverse immunogenic effects, into cancer therapeutics.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0023906</identifier><identifier>PMID: 21912649</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Sequence ; Animals ; Antibodies, Monoclonal - chemistry ; Antibodies, Monoclonal - genetics ; Antibodies, Monoclonal - metabolism ; Antibodies, Monoclonal - pharmacology ; Antibody Specificity ; Anticancer properties ; Antigens ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Bands ; Base Sequence ; Biochemistry ; Biology ; Breast cancer ; Cancer ; Cancer metastasis ; Cancer treatment ; Cell Line, Tumor ; Cell surface ; Chains ; Cloning ; Cloning, Molecular ; E coli ; Female ; Heat shock proteins ; HSP90 Heat-Shock Proteins - immunology ; Hsp90 protein ; Humans ; Hybridomas - cytology ; Immunogenicity ; Immunoglobulin kappa-Chains - chemistry ; Immunoglobulin kappa-Chains - genetics ; Immunoglobulin kappa-Chains - metabolism ; Immunoglobulin kappa-Chains - pharmacology ; Immunoglobulins ; In vivo methods and tests ; Laboratories ; Light ; Localization ; Lung - drug effects ; Lung - pathology ; Lung cancer ; Lungs ; Medicine ; Metastases ; Metastasis ; Mice ; Molecular Sequence Data ; Monoclonal antibodies ; Motility ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Permeability ; Protein Multimerization ; Protein Structure, Quaternary ; Proteins ; Sequence Analysis, DNA ; Single-Chain Antibodies - chemistry ; Single-Chain Antibodies - genetics ; Single-Chain Antibodies - metabolism ; Single-Chain Antibodies - pharmacology ; Tumorigenesis</subject><ispartof>PloS one, 2011-09, Vol.6 (9), p.e23906-e23906</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Sidera et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Sidera et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-a9d46c0409d196505749d432bf8fa42bd42d5448868c5b285badc6ec2dfc240a3</citedby><cites>FETCH-LOGICAL-c691t-a9d46c0409d196505749d432bf8fa42bd42d5448868c5b285badc6ec2dfc240a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164667/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164667/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2104,2930,23873,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21912649$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Driscoll, Paul C.</contributor><creatorcontrib>Sidera, Katerina</creatorcontrib><creatorcontrib>El Hamidieh, Avraam</creatorcontrib><creatorcontrib>Mamalaki, Avgi</creatorcontrib><creatorcontrib>Patsavoudi, Evangelia</creatorcontrib><title>The 4C5 cell-impermeable anti-HSP90 antibody with anti-cancer activity, is composed of a single light chain dimer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>MAb 4C5 is a cell impermeable, anti-HSP90 murine monoclonal antibody, originally produced using hybridoma technology. We have previously shown that mAb 4C5 specifically recognizes both the α- and to a lesser extent the β-isoform of HSP90. Additionally, in vitro and in vivo studies revealed that by selectively inhibiting the function of cell-surface HSP90, mAb 4C5 significantly impairs cancer cell invasion and metastasis. Here we describe the reconstitution of mAb 4C5 into a mouse-human chimera. More importantly we report that mAb 4C5 and consequently its chimeric counterpart are completely devoid of heavy chain and consist only of a functional kappa light chain dimer. The chimeric antibody is shown to retain the original antibody's specificity and functional properties. Thus it is capable of inhibiting the function of surface HSP90, leading to reduced cancer cell invasion in vitro. Finally, we present in vivo evidence showing that the chimeric 4C5 significantly inhibits the metastatic deposit formation of MDA-MB-453 cells into the lungs of SCID mice. These data suggest that a chimeric kappa light chain antibody could be potentially used as an anti-cancer agent, thereby introducing a novel type of antibody fragment, with reduced possible adverse immunogenic effects, into cancer therapeutics.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - chemistry</subject><subject>Antibodies, Monoclonal - genetics</subject><subject>Antibodies, Monoclonal - metabolism</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibody Specificity</subject><subject>Anticancer properties</subject><subject>Antigens</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Bands</subject><subject>Base Sequence</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer metastasis</subject><subject>Cancer treatment</subject><subject>Cell Line, Tumor</subject><subject>Cell surface</subject><subject>Chains</subject><subject>Cloning</subject><subject>Cloning, Molecular</subject><subject>E coli</subject><subject>Female</subject><subject>Heat shock proteins</subject><subject>HSP90 Heat-Shock Proteins - immunology</subject><subject>Hsp90 protein</subject><subject>Humans</subject><subject>Hybridomas - cytology</subject><subject>Immunogenicity</subject><subject>Immunoglobulin kappa-Chains - chemistry</subject><subject>Immunoglobulin kappa-Chains - genetics</subject><subject>Immunoglobulin kappa-Chains - metabolism</subject><subject>Immunoglobulin kappa-Chains - pharmacology</subject><subject>Immunoglobulins</subject><subject>In vivo methods and tests</subject><subject>Laboratories</subject><subject>Light</subject><subject>Localization</subject><subject>Lung - drug effects</subject><subject>Lung - pathology</subject><subject>Lung cancer</subject><subject>Lungs</subject><subject>Medicine</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Monoclonal antibodies</subject><subject>Motility</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Metastasis</subject><subject>Permeability</subject><subject>Protein Multimerization</subject><subject>Protein Structure, Quaternary</subject><subject>Proteins</subject><subject>Sequence Analysis, DNA</subject><subject>Single-Chain Antibodies - chemistry</subject><subject>Single-Chain Antibodies - genetics</subject><subject>Single-Chain Antibodies - metabolism</subject><subject>Single-Chain Antibodies - pharmacology</subject><subject>Tumorigenesis</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1Fv0zAQxyMEYmPwDRBEmgRCIsWOHdd-QZoqYJUmDbHBq3WxncZVEnexM-i3x12zqUF7QH7w6fy7_9l3viR5jdEMkzn-tHZD30Ez27jOzBDKiUDsSXKMBckzliPy9MA-Sl54v0aoIJyx58lRjgXOGRXHyc11bVK6KFJlmiaz7cb0rYGyMSl0wWbnV98FujNLp7fpbxvq_YGCTpk-BRXsrQ3bj6n1qXLtxnmjU1elkHrbraJMY1d1SFUNtku1bU3_MnlWQePNq3E_SX5-_XK9OM8uLr8tF2cXmWIChwyEpkwhioTGghWomNPoIXlZ8QpoXmqa64JSzhlXRZnzogStmFG5rlROEZCT5O1ed9M4L8dqeYkJ4oQUhWCRWO4J7WAtN71tod9KB1beOVy_ktAHqxojS6E4EFExDCUtwJQEEC210Zgo4BpFrc9jtqFsjVamCz00E9HpSWdruXK3kmBGGZtHgfejQO9uBuODbK3fNQU64wYvORe0iJenkTz9h3z8cSO1gnh_21UuplU7TXlG54xzjJmI1OwRKi5tWqviz6ps9E8CPkwCIhPMn7CCwXu5vPrx_-zlryn77oCtDTSh9q4ZgnWdn4J0D6reed-b6qHGGMndYNxXQ-4GQ46DEcPeHPbnIeh-EshfPhkINg</recordid><startdate>20110901</startdate><enddate>20110901</enddate><creator>Sidera, Katerina</creator><creator>El Hamidieh, Avraam</creator><creator>Mamalaki, Avgi</creator><creator>Patsavoudi, Evangelia</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110901</creationdate><title>The 4C5 cell-impermeable anti-HSP90 antibody with anti-cancer activity, is composed of a single light chain dimer</title><author>Sidera, Katerina ; El Hamidieh, Avraam ; Mamalaki, Avgi ; Patsavoudi, Evangelia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-a9d46c0409d196505749d432bf8fa42bd42d5448868c5b285badc6ec2dfc240a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - chemistry</topic><topic>Antibodies, Monoclonal - genetics</topic><topic>Antibodies, Monoclonal - metabolism</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antibody Specificity</topic><topic>Anticancer properties</topic><topic>Antigens</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Bands</topic><topic>Base Sequence</topic><topic>Biochemistry</topic><topic>Biology</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer metastasis</topic><topic>Cancer treatment</topic><topic>Cell Line, Tumor</topic><topic>Cell surface</topic><topic>Chains</topic><topic>Cloning</topic><topic>Cloning, Molecular</topic><topic>E coli</topic><topic>Female</topic><topic>Heat shock proteins</topic><topic>HSP90 Heat-Shock Proteins - immunology</topic><topic>Hsp90 protein</topic><topic>Humans</topic><topic>Hybridomas - cytology</topic><topic>Immunogenicity</topic><topic>Immunoglobulin kappa-Chains - chemistry</topic><topic>Immunoglobulin kappa-Chains - genetics</topic><topic>Immunoglobulin kappa-Chains - metabolism</topic><topic>Immunoglobulin kappa-Chains - pharmacology</topic><topic>Immunoglobulins</topic><topic>In vivo methods and tests</topic><topic>Laboratories</topic><topic>Light</topic><topic>Localization</topic><topic>Lung - drug effects</topic><topic>Lung - pathology</topic><topic>Lung cancer</topic><topic>Lungs</topic><topic>Medicine</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Molecular Sequence Data</topic><topic>Monoclonal antibodies</topic><topic>Motility</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplasm Metastasis</topic><topic>Permeability</topic><topic>Protein Multimerization</topic><topic>Protein Structure, Quaternary</topic><topic>Proteins</topic><topic>Sequence Analysis, DNA</topic><topic>Single-Chain Antibodies - chemistry</topic><topic>Single-Chain Antibodies - genetics</topic><topic>Single-Chain Antibodies - metabolism</topic><topic>Single-Chain Antibodies - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sidera, Katerina</au><au>El Hamidieh, Avraam</au><au>Mamalaki, Avgi</au><au>Patsavoudi, Evangelia</au><au>Driscoll, Paul C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The 4C5 cell-impermeable anti-HSP90 antibody with anti-cancer activity, is composed of a single light chain dimer</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-09-01</date><risdate>2011</risdate><volume>6</volume><issue>9</issue><spage>e23906</spage><epage>e23906</epage><pages>e23906-e23906</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>MAb 4C5 is a cell impermeable, anti-HSP90 murine monoclonal antibody, originally produced using hybridoma technology. We have previously shown that mAb 4C5 specifically recognizes both the α- and to a lesser extent the β-isoform of HSP90. Additionally, in vitro and in vivo studies revealed that by selectively inhibiting the function of cell-surface HSP90, mAb 4C5 significantly impairs cancer cell invasion and metastasis. Here we describe the reconstitution of mAb 4C5 into a mouse-human chimera. More importantly we report that mAb 4C5 and consequently its chimeric counterpart are completely devoid of heavy chain and consist only of a functional kappa light chain dimer. The chimeric antibody is shown to retain the original antibody's specificity and functional properties. Thus it is capable of inhibiting the function of surface HSP90, leading to reduced cancer cell invasion in vitro. Finally, we present in vivo evidence showing that the chimeric 4C5 significantly inhibits the metastatic deposit formation of MDA-MB-453 cells into the lungs of SCID mice. These data suggest that a chimeric kappa light chain antibody could be potentially used as an anti-cancer agent, thereby introducing a novel type of antibody fragment, with reduced possible adverse immunogenic effects, into cancer therapeutics.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21912649</pmid><doi>10.1371/journal.pone.0023906</doi><tpages>e23906</tpages><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Amino Acid Sequence Animals Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - genetics Antibodies, Monoclonal - metabolism Antibodies, Monoclonal - pharmacology Antibody Specificity Anticancer properties Antigens Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Bands Base Sequence Biochemistry Biology Breast cancer Cancer Cancer metastasis Cancer treatment Cell Line, Tumor Cell surface Chains Cloning Cloning, Molecular E coli Female Heat shock proteins HSP90 Heat-Shock Proteins - immunology Hsp90 protein Humans Hybridomas - cytology Immunogenicity Immunoglobulin kappa-Chains - chemistry Immunoglobulin kappa-Chains - genetics Immunoglobulin kappa-Chains - metabolism Immunoglobulin kappa-Chains - pharmacology Immunoglobulins In vivo methods and tests Laboratories Light Localization Lung - drug effects Lung - pathology Lung cancer Lungs Medicine Metastases Metastasis Mice Molecular Sequence Data Monoclonal antibodies Motility Neoplasm Invasiveness Neoplasm Metastasis Permeability Protein Multimerization Protein Structure, Quaternary Proteins Sequence Analysis, DNA Single-Chain Antibodies - chemistry Single-Chain Antibodies - genetics Single-Chain Antibodies - metabolism Single-Chain Antibodies - pharmacology Tumorigenesis |
title | The 4C5 cell-impermeable anti-HSP90 antibody with anti-cancer activity, is composed of a single light chain dimer |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-05T17%3A25%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%204C5%20cell-impermeable%20anti-HSP90%20antibody%20with%20anti-cancer%20activity,%20is%20composed%20of%20a%20single%20light%20chain%20dimer&rft.jtitle=PloS%20one&rft.au=Sidera,%20Katerina&rft.date=2011-09-01&rft.volume=6&rft.issue=9&rft.spage=e23906&rft.epage=e23906&rft.pages=e23906-e23906&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0023906&rft_dat=%3Cgale_plos_%3EA476881169%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1308335596&rft_id=info:pmid/21912649&rft_galeid=A476881169&rft_doaj_id=oai_doaj_org_article_b9c8a39f61ab45aeb3a04bded13ca8d0&rfr_iscdi=true |