Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction
Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressi...
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Veröffentlicht in: | Journal of immunotherapy 2007-10, Vol.30 (7), p.684-693 |
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creator | TURATTI, Fabio FIGINI, Mariangela BALLADORE, Emanuela ALBERTI, Paola CASALINI, Patrizia MARKS, James D CANEVARI, Silvana MEZZANZANICA, Delia |
description | Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressing a tumor-associated antigens. We transduced human PBMC with 2 fully human CIRs that trigger through the zeta-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts. |
doi_str_mv | 10.1097/cji.0b013e3180de5d90 |
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We transduced human PBMC with 2 fully human CIRs that trigger through the zeta-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts.</description><identifier>ISSN: 1524-9557</identifier><identifier>ISSN: 1053-8550</identifier><identifier>EISSN: 1537-4513</identifier><identifier>DOI: 10.1097/cji.0b013e3180de5d90</identifier><identifier>PMID: 17893561</identifier><identifier>CODEN: JOIMF8</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott</publisher><subject>Antibody Affinity ; Antigens, Neoplasm - immunology ; Antineoplastic agents ; Biological and medical sciences ; Cell Line ; Cell Line, Tumor ; Cytotoxicity, Immunologic ; Humans ; Immunoglobulin Variable Region - immunology ; Immunotherapy ; Leukocytes, Mononuclear - immunology ; Medical sciences ; Pharmacology. Drug treatments ; Receptor, ErbB-2 - genetics ; Receptor, ErbB-2 - immunology ; Receptors, Immunologic - genetics ; Receptors, Immunologic - immunology ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - immunology ; T-Lymphocytes, Cytotoxic - immunology ; Transduction, Genetic</subject><ispartof>Journal of immunotherapy, 2007-10, Vol.30 (7), p.684-693</ispartof><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-244c96debe17393bfaaecd1f633797684b37d4e464a52ea550a79e67edc26aa73</citedby><cites>FETCH-LOGICAL-c463t-244c96debe17393bfaaecd1f633797684b37d4e464a52ea550a79e67edc26aa73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19113267$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17893561$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>TURATTI, Fabio</creatorcontrib><creatorcontrib>FIGINI, Mariangela</creatorcontrib><creatorcontrib>BALLADORE, Emanuela</creatorcontrib><creatorcontrib>ALBERTI, Paola</creatorcontrib><creatorcontrib>CASALINI, Patrizia</creatorcontrib><creatorcontrib>MARKS, James D</creatorcontrib><creatorcontrib>CANEVARI, Silvana</creatorcontrib><creatorcontrib>MEZZANZANICA, Delia</creatorcontrib><title>Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction</title><title>Journal of immunotherapy</title><addtitle>J Immunother</addtitle><description>Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressing a tumor-associated antigens. We transduced human PBMC with 2 fully human CIRs that trigger through the zeta-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts.</description><subject>Antibody Affinity</subject><subject>Antigens, Neoplasm - immunology</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cytotoxicity, Immunologic</subject><subject>Humans</subject><subject>Immunoglobulin Variable Region - immunology</subject><subject>Immunotherapy</subject><subject>Leukocytes, Mononuclear - immunology</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Receptor, ErbB-2 - immunology</subject><subject>Receptors, Immunologic - genetics</subject><subject>Receptors, Immunologic - immunology</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - immunology</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><subject>Transduction, Genetic</subject><issn>1524-9557</issn><issn>1053-8550</issn><issn>1537-4513</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1rFTEUhoMotlb_gUg2upua79ws5WI_pCCUuh4yyZk2ZSa5JpmL92_0FzvTDhbc6CqBPM97DnkRek_JKSVGf3b34ZR0hHLgdEM8SG_IC3RMJdeNkJS_XO5MNEZKfYTelHJPCFNMsNfoiOqN4VLRY_RwDT5kcBU8tq6GfagHnHp8N402YhtrqNOYMnZ3YYQcHA7jOEXAswK7mnLBoeDbtIcc54Tu8KjcwqL6PxCGX7sMpYQU8QB7GMrjs-37ENd5IVbIywIpvkWvejsUeLeeJ-jH2deb7UVz9f38cvvlqnFC8dowIZxRHjqgmhve9daC87RXnGuj1UZ0XHsBQgkrGVgpidUGlAbvmLJW8xP06Sl3l9PPCUptx1AcDIONkKbSqg2nyyf9E2Rkmcf0f4BSUy3ZDIon0OVUSoa-3eUw2nxoKWmXdtvtt8v273Zn7cOaP3Uj-GdprXMGPq6ALc4OfbbRhfLMGUo5U5r_BrppssM</recordid><startdate>20071001</startdate><enddate>20071001</enddate><creator>TURATTI, Fabio</creator><creator>FIGINI, Mariangela</creator><creator>BALLADORE, Emanuela</creator><creator>ALBERTI, Paola</creator><creator>CASALINI, Patrizia</creator><creator>MARKS, James D</creator><creator>CANEVARI, Silvana</creator><creator>MEZZANZANICA, Delia</creator><general>Lippincott</general><scope>IQODW</scope><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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20071001</creationdate><title>Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction</title><author>TURATTI, Fabio ; FIGINI, Mariangela ; BALLADORE, Emanuela ; ALBERTI, Paola ; CASALINI, Patrizia ; MARKS, James D ; CANEVARI, Silvana ; MEZZANZANICA, Delia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-244c96debe17393bfaaecd1f633797684b37d4e464a52ea550a79e67edc26aa73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Antibody Affinity</topic><topic>Antigens, Neoplasm - immunology</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cytotoxicity, Immunologic</topic><topic>Humans</topic><topic>Immunoglobulin Variable Region - immunology</topic><topic>Immunotherapy</topic><topic>Leukocytes, Mononuclear - immunology</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>Receptor, ErbB-2 - immunology</topic><topic>Receptors, Immunologic - genetics</topic><topic>Receptors, Immunologic - immunology</topic><topic>Recombinant Fusion Proteins - genetics</topic><topic>Recombinant Fusion Proteins - immunology</topic><topic>T-Lymphocytes, Cytotoxic - immunology</topic><topic>Transduction, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>TURATTI, Fabio</creatorcontrib><creatorcontrib>FIGINI, Mariangela</creatorcontrib><creatorcontrib>BALLADORE, Emanuela</creatorcontrib><creatorcontrib>ALBERTI, Paola</creatorcontrib><creatorcontrib>CASALINI, Patrizia</creatorcontrib><creatorcontrib>MARKS, James D</creatorcontrib><creatorcontrib>CANEVARI, Silvana</creatorcontrib><creatorcontrib>MEZZANZANICA, Delia</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of immunotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>TURATTI, Fabio</au><au>FIGINI, Mariangela</au><au>BALLADORE, Emanuela</au><au>ALBERTI, Paola</au><au>CASALINI, Patrizia</au><au>MARKS, James D</au><au>CANEVARI, Silvana</au><au>MEZZANZANICA, Delia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction</atitle><jtitle>Journal of immunotherapy</jtitle><addtitle>J Immunother</addtitle><date>2007-10-01</date><risdate>2007</risdate><volume>30</volume><issue>7</issue><spage>684</spage><epage>693</epage><pages>684-693</pages><issn>1524-9557</issn><issn>1053-8550</issn><eissn>1537-4513</eissn><coden>JOIMF8</coden><abstract>Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressing a tumor-associated antigens. We transduced human PBMC with 2 fully human CIRs that trigger through the zeta-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts.</abstract><cop>Hagerstown, MD</cop><cop>Philadelphia,PA</cop><pub>Lippincott</pub><pmid>17893561</pmid><doi>10.1097/cji.0b013e3180de5d90</doi><tpages>10</tpages></addata></record> |
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subjects | Antibody Affinity Antigens, Neoplasm - immunology Antineoplastic agents Biological and medical sciences Cell Line Cell Line, Tumor Cytotoxicity, Immunologic Humans Immunoglobulin Variable Region - immunology Immunotherapy Leukocytes, Mononuclear - immunology Medical sciences Pharmacology. Drug treatments Receptor, ErbB-2 - genetics Receptor, ErbB-2 - immunology Receptors, Immunologic - genetics Receptors, Immunologic - immunology Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - immunology T-Lymphocytes, Cytotoxic - immunology Transduction, Genetic |
title | Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction |
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