Preclinical Evaluation of a Recombinant Anti-Prostate Specific Membrane Antigen Single-Chain Immunotoxin Against Prostate Cancer
The prostate-specific membrane antigen (PSMA) is abundantly expressed on prostate cancer epithelial cells and its expression correlates with tumor progression. Therefore, a specific immunotherapy against this antigen may be a novel therapeutic option for the management of prostate cancer. We generat...
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| Veröffentlicht in: | Journal of immunotherapy 2010-04, Vol.33 (3), p.262-271 |
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| creator | WOLF, Philipp ALT, Karen WETTERAUER, David BÜHLER, Patrick GIERSCHNER, Dorothee KATZENWADEL, Arndt WETTERAUER, Ulrich ELSÄSSER-BEILE, Ursula |
| description | The prostate-specific membrane antigen (PSMA) is abundantly expressed on prostate cancer epithelial cells and its expression correlates with tumor progression. Therefore, a specific immunotherapy against this antigen may be a novel therapeutic option for the management of prostate cancer. We generated an anti-PSMA single-chain antibody fragment (scFv), called D7, by phage display from the monoclonal antibody 3/F11. By C-terminal ligation of the toxic domain of Pseudomonas Exotoxin A (PE40) to the genes of D7, the immunotoxin D7-PE40 was generated. D7 and D7-PE40 specifically bound to PSMA transfectants and to the PSMA expressing prostate cancer cell line C4-2. In addition, D7-PE40 showed a high serum stability and induced a 50% reduction of viability (IC50) in C4-2 cells at a concentration of 140 pM. In vivo, D7-PE40 was well tolerated in SCID mice up to a single dose of 20 microg, whereas higher doses induced severe hepatotoxicity with deaths of the animals. Immunotoxin treatment of mice bearing C4-2 tumor xenografts caused a significant inhibition of tumor growth, whereas mice with PSMA-negative DU 145 tumors remained unaffected. Owing to its high and specific cytotoxicity and its capability to inhibit prostate tumor growth in vivo the immunotoxin D7-PE40 represents a promising candidate for the immunotherapy of prostate cancer. |
| doi_str_mv | 10.1097/CJI.0b013e3181c5495c |
| format | Article |
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Therefore, a specific immunotherapy against this antigen may be a novel therapeutic option for the management of prostate cancer. We generated an anti-PSMA single-chain antibody fragment (scFv), called D7, by phage display from the monoclonal antibody 3/F11. By C-terminal ligation of the toxic domain of Pseudomonas Exotoxin A (PE40) to the genes of D7, the immunotoxin D7-PE40 was generated. D7 and D7-PE40 specifically bound to PSMA transfectants and to the PSMA expressing prostate cancer cell line C4-2. In addition, D7-PE40 showed a high serum stability and induced a 50% reduction of viability (IC50) in C4-2 cells at a concentration of 140 pM. In vivo, D7-PE40 was well tolerated in SCID mice up to a single dose of 20 microg, whereas higher doses induced severe hepatotoxicity with deaths of the animals. Immunotoxin treatment of mice bearing C4-2 tumor xenografts caused a significant inhibition of tumor growth, whereas mice with PSMA-negative DU 145 tumors remained unaffected. Owing to its high and specific cytotoxicity and its capability to inhibit prostate tumor growth in vivo the immunotoxin D7-PE40 represents a promising candidate for the immunotherapy of prostate cancer.</description><identifier>ISSN: 1524-9557</identifier><identifier>ISSN: 1053-8550</identifier><identifier>EISSN: 1537-4513</identifier><identifier>DOI: 10.1097/CJI.0b013e3181c5495c</identifier><identifier>PMID: 20445346</identifier><identifier>CODEN: JOIMF8</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>ADP Ribose Transferases - genetics ; ADP Ribose Transferases - immunology ; Animals ; Antigens, Surface - genetics ; Antigens, Surface - immunology ; Antineoplastic agents ; Bacterial Toxins - genetics ; Bacterial Toxins - immunology ; Biological and medical sciences ; Cell Line ; Cell Line, Tumor ; Cell Survival - drug effects ; Cell Survival - immunology ; Drug Screening Assays, Antitumor ; Exotoxins - genetics ; Exotoxins - immunology ; Glutamate Carboxypeptidase II - genetics ; Glutamate Carboxypeptidase II - immunology ; Gynecology. Andrology. Obstetrics ; Humans ; Immunotherapy ; Immunotoxins - genetics ; Immunotoxins - immunology ; Immunotoxins - pharmacology ; Male ; Male genital diseases ; Medical sciences ; Mice ; Mice, SCID ; Nephrology. Urinary tract diseases ; Pharmacology. Drug treatments ; Prostatic Neoplasms - immunology ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - prevention & control ; Pseudomonas ; Pseudomonas aeruginosa Exotoxin A ; Recombinant Proteins - immunology ; Single-Chain Antibodies - genetics ; Single-Chain Antibodies - immunology ; Tumor Burden - drug effects ; Tumors ; Tumors of the urinary system ; Urinary tract. Prostate gland ; Virulence Factors - genetics ; Virulence Factors - immunology ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of immunotherapy, 2010-04, Vol.33 (3), p.262-271</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-9c5a1e58007505a603ca36d885947ba5631323a0d12696c88041c7113f3669c73</citedby><cites>FETCH-LOGICAL-c400t-9c5a1e58007505a603ca36d885947ba5631323a0d12696c88041c7113f3669c73</cites></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=22550137$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20445346$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>WOLF, Philipp</creatorcontrib><creatorcontrib>ALT, Karen</creatorcontrib><creatorcontrib>WETTERAUER, David</creatorcontrib><creatorcontrib>BÜHLER, Patrick</creatorcontrib><creatorcontrib>GIERSCHNER, Dorothee</creatorcontrib><creatorcontrib>KATZENWADEL, Arndt</creatorcontrib><creatorcontrib>WETTERAUER, Ulrich</creatorcontrib><creatorcontrib>ELSÄSSER-BEILE, Ursula</creatorcontrib><title>Preclinical Evaluation of a Recombinant Anti-Prostate Specific Membrane Antigen Single-Chain Immunotoxin Against Prostate Cancer</title><title>Journal of immunotherapy</title><addtitle>J Immunother</addtitle><description>The prostate-specific membrane antigen (PSMA) is abundantly expressed on prostate cancer epithelial cells and its expression correlates with tumor progression. Therefore, a specific immunotherapy against this antigen may be a novel therapeutic option for the management of prostate cancer. We generated an anti-PSMA single-chain antibody fragment (scFv), called D7, by phage display from the monoclonal antibody 3/F11. By C-terminal ligation of the toxic domain of Pseudomonas Exotoxin A (PE40) to the genes of D7, the immunotoxin D7-PE40 was generated. D7 and D7-PE40 specifically bound to PSMA transfectants and to the PSMA expressing prostate cancer cell line C4-2. In addition, D7-PE40 showed a high serum stability and induced a 50% reduction of viability (IC50) in C4-2 cells at a concentration of 140 pM. In vivo, D7-PE40 was well tolerated in SCID mice up to a single dose of 20 microg, whereas higher doses induced severe hepatotoxicity with deaths of the animals. Immunotoxin treatment of mice bearing C4-2 tumor xenografts caused a significant inhibition of tumor growth, whereas mice with PSMA-negative DU 145 tumors remained unaffected. Owing to its high and specific cytotoxicity and its capability to inhibit prostate tumor growth in vivo the immunotoxin D7-PE40 represents a promising candidate for the immunotherapy of prostate cancer.</description><subject>ADP Ribose Transferases - genetics</subject><subject>ADP Ribose Transferases - immunology</subject><subject>Animals</subject><subject>Antigens, Surface - genetics</subject><subject>Antigens, Surface - immunology</subject><subject>Antineoplastic agents</subject><subject>Bacterial Toxins - genetics</subject><subject>Bacterial Toxins - immunology</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - immunology</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Exotoxins - genetics</subject><subject>Exotoxins - immunology</subject><subject>Glutamate Carboxypeptidase II - genetics</subject><subject>Glutamate Carboxypeptidase II - immunology</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Immunotoxins - genetics</subject><subject>Immunotoxins - immunology</subject><subject>Immunotoxins - pharmacology</subject><subject>Male</subject><subject>Male genital diseases</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Pharmacology. Drug treatments</subject><subject>Prostatic Neoplasms - immunology</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Prostatic Neoplasms - prevention & control</subject><subject>Pseudomonas</subject><subject>Pseudomonas aeruginosa Exotoxin A</subject><subject>Recombinant Proteins - immunology</subject><subject>Single-Chain Antibodies - genetics</subject><subject>Single-Chain Antibodies - immunology</subject><subject>Tumor Burden - drug effects</subject><subject>Tumors</subject><subject>Tumors of the urinary system</subject><subject>Urinary tract. Prostate gland</subject><subject>Virulence Factors - genetics</subject><subject>Virulence Factors - immunology</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1524-9557</issn><issn>1053-8550</issn><issn>1537-4513</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1P3DAQhq2qVaEL_6BCvlQ9BcbfyXEVUboVCMTHOXJmna1R4iyxU5Vbf3pN2VKJS08e2c-8Y_sh5CODYwaVOam_rY6hBSacYCVDJSuFb8g-U8IUUjHx9qnmsqiUMnvkQ4z3AFxzyd-TPQ5SKiH1Pvl1NTnsffBoe3r6w_azTX4MdOyopdcOx6H1wYZElyH54moaY7LJ0ZutQ995pBduaCcb3J_zjQv0xodN74r6u_WBroZhDmMaf-Z6uck7MdGXjNoGdNMBedfZPrrD3bogd19Ob-uvxfnl2apenhcoAVJRobLMqRLAKFBWg0Ar9LosVSVNa5UWTHBhYc24rjSWJUiGhjHRCa0rNGJBPj_nbqfxYXYxNYOP6Po-X36cY1MyoxkDxf9LGpmnccjZCyKfScxvipPrmu3kBzs9NgyaJ0lNltS8lpTbjnYD5nZw65emv1Yy8GkH2Ji9dPmD0cd_HFcqRxrxGwn0mmw</recordid><startdate>20100401</startdate><enddate>20100401</enddate><creator>WOLF, Philipp</creator><creator>ALT, Karen</creator><creator>WETTERAUER, David</creator><creator>BÜHLER, Patrick</creator><creator>GIERSCHNER, Dorothee</creator><creator>KATZENWADEL, Arndt</creator><creator>WETTERAUER, Ulrich</creator><creator>ELSÄSSER-BEILE, Ursula</creator><general>Lippincott Williams & Wilkins</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>7QL</scope><scope>7T5</scope><scope>C1K</scope><scope>H94</scope></search><sort><creationdate>20100401</creationdate><title>Preclinical Evaluation of a Recombinant Anti-Prostate Specific Membrane Antigen Single-Chain Immunotoxin Against Prostate Cancer</title><author>WOLF, Philipp ; ALT, Karen ; WETTERAUER, David ; BÜHLER, Patrick ; GIERSCHNER, Dorothee ; KATZENWADEL, Arndt ; WETTERAUER, Ulrich ; ELSÄSSER-BEILE, Ursula</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-9c5a1e58007505a603ca36d885947ba5631323a0d12696c88041c7113f3669c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>ADP Ribose Transferases - genetics</topic><topic>ADP Ribose Transferases - immunology</topic><topic>Animals</topic><topic>Antigens, Surface - genetics</topic><topic>Antigens, Surface - immunology</topic><topic>Antineoplastic agents</topic><topic>Bacterial Toxins - genetics</topic><topic>Bacterial Toxins - immunology</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - immunology</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Exotoxins - genetics</topic><topic>Exotoxins - immunology</topic><topic>Glutamate Carboxypeptidase II - genetics</topic><topic>Glutamate Carboxypeptidase II - immunology</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Immunotoxins - genetics</topic><topic>Immunotoxins - immunology</topic><topic>Immunotoxins - pharmacology</topic><topic>Male</topic><topic>Male genital diseases</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Pharmacology. Drug treatments</topic><topic>Prostatic Neoplasms - immunology</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Prostatic Neoplasms - prevention & control</topic><topic>Pseudomonas</topic><topic>Pseudomonas aeruginosa Exotoxin A</topic><topic>Recombinant Proteins - immunology</topic><topic>Single-Chain Antibodies - genetics</topic><topic>Single-Chain Antibodies - immunology</topic><topic>Tumor Burden - drug effects</topic><topic>Tumors</topic><topic>Tumors of the urinary system</topic><topic>Urinary tract. Prostate gland</topic><topic>Virulence Factors - genetics</topic><topic>Virulence Factors - immunology</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>WOLF, Philipp</creatorcontrib><creatorcontrib>ALT, Karen</creatorcontrib><creatorcontrib>WETTERAUER, David</creatorcontrib><creatorcontrib>BÜHLER, Patrick</creatorcontrib><creatorcontrib>GIERSCHNER, Dorothee</creatorcontrib><creatorcontrib>KATZENWADEL, Arndt</creatorcontrib><creatorcontrib>WETTERAUER, Ulrich</creatorcontrib><creatorcontrib>ELSÄSSER-BEILE, Ursula</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>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Journal of immunotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>WOLF, Philipp</au><au>ALT, Karen</au><au>WETTERAUER, David</au><au>BÜHLER, Patrick</au><au>GIERSCHNER, Dorothee</au><au>KATZENWADEL, Arndt</au><au>WETTERAUER, Ulrich</au><au>ELSÄSSER-BEILE, Ursula</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preclinical Evaluation of a Recombinant Anti-Prostate Specific Membrane Antigen Single-Chain Immunotoxin Against Prostate Cancer</atitle><jtitle>Journal of immunotherapy</jtitle><addtitle>J Immunother</addtitle><date>2010-04-01</date><risdate>2010</risdate><volume>33</volume><issue>3</issue><spage>262</spage><epage>271</epage><pages>262-271</pages><issn>1524-9557</issn><issn>1053-8550</issn><eissn>1537-4513</eissn><coden>JOIMF8</coden><abstract>The prostate-specific membrane antigen (PSMA) is abundantly expressed on prostate cancer epithelial cells and its expression correlates with tumor progression. Therefore, a specific immunotherapy against this antigen may be a novel therapeutic option for the management of prostate cancer. We generated an anti-PSMA single-chain antibody fragment (scFv), called D7, by phage display from the monoclonal antibody 3/F11. By C-terminal ligation of the toxic domain of Pseudomonas Exotoxin A (PE40) to the genes of D7, the immunotoxin D7-PE40 was generated. D7 and D7-PE40 specifically bound to PSMA transfectants and to the PSMA expressing prostate cancer cell line C4-2. In addition, D7-PE40 showed a high serum stability and induced a 50% reduction of viability (IC50) in C4-2 cells at a concentration of 140 pM. In vivo, D7-PE40 was well tolerated in SCID mice up to a single dose of 20 microg, whereas higher doses induced severe hepatotoxicity with deaths of the animals. Immunotoxin treatment of mice bearing C4-2 tumor xenografts caused a significant inhibition of tumor growth, whereas mice with PSMA-negative DU 145 tumors remained unaffected. Owing to its high and specific cytotoxicity and its capability to inhibit prostate tumor growth in vivo the immunotoxin D7-PE40 represents a promising candidate for the immunotherapy of prostate cancer.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>20445346</pmid><doi>10.1097/CJI.0b013e3181c5495c</doi><tpages>10</tpages></addata></record> |
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| subjects | ADP Ribose Transferases - genetics ADP Ribose Transferases - immunology Animals Antigens, Surface - genetics Antigens, Surface - immunology Antineoplastic agents Bacterial Toxins - genetics Bacterial Toxins - immunology Biological and medical sciences Cell Line Cell Line, Tumor Cell Survival - drug effects Cell Survival - immunology Drug Screening Assays, Antitumor Exotoxins - genetics Exotoxins - immunology Glutamate Carboxypeptidase II - genetics Glutamate Carboxypeptidase II - immunology Gynecology. Andrology. Obstetrics Humans Immunotherapy Immunotoxins - genetics Immunotoxins - immunology Immunotoxins - pharmacology Male Male genital diseases Medical sciences Mice Mice, SCID Nephrology. Urinary tract diseases Pharmacology. Drug treatments Prostatic Neoplasms - immunology Prostatic Neoplasms - pathology Prostatic Neoplasms - prevention & control Pseudomonas Pseudomonas aeruginosa Exotoxin A Recombinant Proteins - immunology Single-Chain Antibodies - genetics Single-Chain Antibodies - immunology Tumor Burden - drug effects Tumors Tumors of the urinary system Urinary tract. Prostate gland Virulence Factors - genetics Virulence Factors - immunology Xenograft Model Antitumor Assays |
| title | Preclinical Evaluation of a Recombinant Anti-Prostate Specific Membrane Antigen Single-Chain Immunotoxin Against Prostate Cancer |
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