Generation of an artificial human B cell line test system using Transpo-mAbTM technology to evaluate the therapeutic efficacy of novel antigen-specific fusion proteins
The antigen-specific targeting of autoreactive B cells via their unique B cell receptors (BCRs) is a novel and promising alternative to the systemic suppression of humoral immunity. We generated and characterized cytolytic fusion proteins based on an existing immunotoxin comprising tetanus toxoid fr...
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| Veröffentlicht in: | PloS one 2017-07, Vol.12 (7), p.e0180305 |
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| creator | Klose, Diana Woitok, Mira Niesen, Judith Beerli, Roger R Grawunder, Ulf Fischer, Rainer Barth, Stefan Fendel, Rolf Nachreiner, Thomas |
| description | The antigen-specific targeting of autoreactive B cells via their unique B cell receptors (BCRs) is a novel and promising alternative to the systemic suppression of humoral immunity. We generated and characterized cytolytic fusion proteins based on an existing immunotoxin comprising tetanus toxoid fragment C (TTC) as the targeting component and the modified Pseudomonas aeruginosa exotoxin A (ETA') as the cytotoxic component. The immunotoxin was reconfigured to replace ETA' with either the granzyme B mutant R201K or MAPTau as human effector domains. The novel cytolytic fusion proteins were characterized with a recombinant human lymphocytic cell line developed using Transpo-mAb™ technology. Genes encoding a chimeric TTC-reactive immunoglobulin G were successfully integrated into the genome of the precursor B cell line REH so that the cells could present TTC-reactive BCRs on their surface. These cells were used to investigate the specific cytotoxicity of GrB(R201K)-TTC and TTC-MAPTau, revealing that the serpin proteinase inhibitor 9-resistant granzyme B R201K mutant induced apoptosis specifically in the lymphocytic cell line. Our data confirm that antigen-based fusion proteins containing granzyme B (R201K) are suitable candidates for the depletion of autoreactive B cells. |
| doi_str_mv | 10.1371/journal.pone.0180305 |
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We generated and characterized cytolytic fusion proteins based on an existing immunotoxin comprising tetanus toxoid fragment C (TTC) as the targeting component and the modified Pseudomonas aeruginosa exotoxin A (ETA') as the cytotoxic component. The immunotoxin was reconfigured to replace ETA' with either the granzyme B mutant R201K or MAPTau as human effector domains. The novel cytolytic fusion proteins were characterized with a recombinant human lymphocytic cell line developed using Transpo-mAb™ technology. Genes encoding a chimeric TTC-reactive immunoglobulin G were successfully integrated into the genome of the precursor B cell line REH so that the cells could present TTC-reactive BCRs on their surface. These cells were used to investigate the specific cytotoxicity of GrB(R201K)-TTC and TTC-MAPTau, revealing that the serpin proteinase inhibitor 9-resistant granzyme B R201K mutant induced apoptosis specifically in the lymphocytic cell line. Our data confirm that antigen-based fusion proteins containing granzyme B (R201K) are suitable candidates for the depletion of autoreactive B cells.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0180305</identifier><identifier>PMID: 28704435</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antigen presentation ; Apoptosis ; Autoimmune diseases ; B-Lymphocytes - cytology ; B-Lymphocytes - metabolism ; Biology and Life Sciences ; Biotechnology ; Cancer therapies ; Cell Engineering - methods ; Cell Line, Tumor ; Cytotoxicity ; Exotoxin A ; Genomes ; Granzyme B ; Granzymes - genetics ; Granzymes - metabolism ; Hospitals ; Humans ; Humoral immunity ; Immune system ; Immunity ; Immunity (humoral) ; Immunoglobulin G ; Immunoglobulins ; Immunology ; Immunotherapy ; Immunotoxins ; Immunotoxins - metabolism ; Lymphocytes ; Lymphocytes B ; Medicine ; Medicine and Health Sciences ; Molecular biology ; Proteinase ; Proteinase inhibitor 9 ; Proteinase inhibitors ; Proteins ; Pseudomonas aeruginosa ; Receptors ; Receptors, Antigen, B-Cell - immunology ; Recombinant Fusion Proteins - immunology ; Recombinant Fusion Proteins - metabolism ; Research and Analysis Methods ; Single-Chain Antibodies - metabolism ; Stem cells ; T cell receptors ; Technology ; Technology assessment ; Technology utilization ; Tetanus ; Tetanus Toxoid - immunology ; Tetanus Toxoid - metabolism ; Toxicity ; Vaccines</subject><ispartof>PloS one, 2017-07, Vol.12 (7), p.e0180305</ispartof><rights>2017 Klose et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2017 Klose et al 2017 Klose et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4415-fdc53bf1f4be267ba1c465303e7a513ec3b198142de214754b47b4e81b29afcb3</citedby><cites>FETCH-LOGICAL-c4415-fdc53bf1f4be267ba1c465303e7a513ec3b198142de214754b47b4e81b29afcb3</cites><orcidid>0000-0003-4716-0311</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509223/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509223/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28704435$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bernardino de la Serna, Jorge</contributor><creatorcontrib>Klose, Diana</creatorcontrib><creatorcontrib>Woitok, Mira</creatorcontrib><creatorcontrib>Niesen, Judith</creatorcontrib><creatorcontrib>Beerli, Roger R</creatorcontrib><creatorcontrib>Grawunder, Ulf</creatorcontrib><creatorcontrib>Fischer, Rainer</creatorcontrib><creatorcontrib>Barth, Stefan</creatorcontrib><creatorcontrib>Fendel, Rolf</creatorcontrib><creatorcontrib>Nachreiner, Thomas</creatorcontrib><title>Generation of an artificial human B cell line test system using Transpo-mAbTM technology to evaluate the therapeutic efficacy of novel antigen-specific fusion proteins</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The antigen-specific targeting of autoreactive B cells via their unique B cell receptors (BCRs) is a novel and promising alternative to the systemic suppression of humoral immunity. 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Our data confirm that antigen-based fusion proteins containing granzyme B (R201K) are suitable candidates for the depletion of autoreactive B cells.</description><subject>Antigen presentation</subject><subject>Apoptosis</subject><subject>Autoimmune diseases</subject><subject>B-Lymphocytes - cytology</subject><subject>B-Lymphocytes - metabolism</subject><subject>Biology and Life Sciences</subject><subject>Biotechnology</subject><subject>Cancer therapies</subject><subject>Cell Engineering - methods</subject><subject>Cell Line, Tumor</subject><subject>Cytotoxicity</subject><subject>Exotoxin A</subject><subject>Genomes</subject><subject>Granzyme B</subject><subject>Granzymes - genetics</subject><subject>Granzymes - metabolism</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Humoral immunity</subject><subject>Immune system</subject><subject>Immunity</subject><subject>Immunity (humoral)</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulins</subject><subject>Immunology</subject><subject>Immunotherapy</subject><subject>Immunotoxins</subject><subject>Immunotoxins - 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cytology</topic><topic>B-Lymphocytes - metabolism</topic><topic>Biology and Life Sciences</topic><topic>Biotechnology</topic><topic>Cancer therapies</topic><topic>Cell Engineering - methods</topic><topic>Cell Line, Tumor</topic><topic>Cytotoxicity</topic><topic>Exotoxin A</topic><topic>Genomes</topic><topic>Granzyme B</topic><topic>Granzymes - genetics</topic><topic>Granzymes - metabolism</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Humoral immunity</topic><topic>Immune system</topic><topic>Immunity</topic><topic>Immunity (humoral)</topic><topic>Immunoglobulin G</topic><topic>Immunoglobulins</topic><topic>Immunology</topic><topic>Immunotherapy</topic><topic>Immunotoxins</topic><topic>Immunotoxins - metabolism</topic><topic>Lymphocytes</topic><topic>Lymphocytes B</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Molecular biology</topic><topic>Proteinase</topic><topic>Proteinase inhibitor 9</topic><topic>Proteinase inhibitors</topic><topic>Proteins</topic><topic>Pseudomonas aeruginosa</topic><topic>Receptors</topic><topic>Receptors, Antigen, B-Cell - 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We generated and characterized cytolytic fusion proteins based on an existing immunotoxin comprising tetanus toxoid fragment C (TTC) as the targeting component and the modified Pseudomonas aeruginosa exotoxin A (ETA') as the cytotoxic component. The immunotoxin was reconfigured to replace ETA' with either the granzyme B mutant R201K or MAPTau as human effector domains. The novel cytolytic fusion proteins were characterized with a recombinant human lymphocytic cell line developed using Transpo-mAb™ technology. Genes encoding a chimeric TTC-reactive immunoglobulin G were successfully integrated into the genome of the precursor B cell line REH so that the cells could present TTC-reactive BCRs on their surface. These cells were used to investigate the specific cytotoxicity of GrB(R201K)-TTC and TTC-MAPTau, revealing that the serpin proteinase inhibitor 9-resistant granzyme B R201K mutant induced apoptosis specifically in the lymphocytic cell line. Our data confirm that antigen-based fusion proteins containing granzyme B (R201K) are suitable candidates for the depletion of autoreactive B cells.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28704435</pmid><doi>10.1371/journal.pone.0180305</doi><orcidid>https://orcid.org/0000-0003-4716-0311</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-07, Vol.12 (7), p.e0180305 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1919490109 |
| source | Open Access: PubMed Central; PLoS; MEDLINE; Full-Text Journals in Chemistry (Open access); DOAJ Directory of Open Access Journals; EZB Electronic Journals Library |
| subjects | Antigen presentation Apoptosis Autoimmune diseases B-Lymphocytes - cytology B-Lymphocytes - metabolism Biology and Life Sciences Biotechnology Cancer therapies Cell Engineering - methods Cell Line, Tumor Cytotoxicity Exotoxin A Genomes Granzyme B Granzymes - genetics Granzymes - metabolism Hospitals Humans Humoral immunity Immune system Immunity Immunity (humoral) Immunoglobulin G Immunoglobulins Immunology Immunotherapy Immunotoxins Immunotoxins - metabolism Lymphocytes Lymphocytes B Medicine Medicine and Health Sciences Molecular biology Proteinase Proteinase inhibitor 9 Proteinase inhibitors Proteins Pseudomonas aeruginosa Receptors Receptors, Antigen, B-Cell - immunology Recombinant Fusion Proteins - immunology Recombinant Fusion Proteins - metabolism Research and Analysis Methods Single-Chain Antibodies - metabolism Stem cells T cell receptors Technology Technology assessment Technology utilization Tetanus Tetanus Toxoid - immunology Tetanus Toxoid - metabolism Toxicity Vaccines |
| title | Generation of an artificial human B cell line test system using Transpo-mAbTM technology to evaluate the therapeutic efficacy of novel antigen-specific fusion proteins |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T18%3A08%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Generation%20of%20an%20artificial%20human%20B%20cell%20line%20test%20system%20using%20Transpo-mAbTM%20technology%20to%20evaluate%20the%20therapeutic%20efficacy%20of%20novel%20antigen-specific%20fusion%20proteins&rft.jtitle=PloS%20one&rft.au=Klose,%20Diana&rft.date=2017-07-01&rft.volume=12&rft.issue=7&rft.spage=e0180305&rft.pages=e0180305-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0180305&rft_dat=%3Cproquest_plos_%3E1919490109%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1919490109&rft_id=info:pmid/28704435&rft_doaj_id=oai_doaj_org_article_3d8df7af4837489b88b6d6e8d638ee06&rfr_iscdi=true |