A humanized minipig model for the toxicological testing of therapeutic recombinant antibodies
The safety of most human recombinant proteins can be evaluated in transgenic mice tolerant to specific human proteins. However, owing to insufficient genetic diversity and to fundamental differences in immune mechanisms, small-animal models of human diseases are often unsuitable for immunogenicity t...
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| Veröffentlicht in: | Nature biomedical engineering 2022-11, Vol.6 (11), p.1248-1256 |
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| creator | Flisikowska, Tatiana Egli, Jerome Flisikowski, Krzysztof Stumbaum, Marlene Küng, Erich Ebeling, Martin Schmucki, Roland Georges, Guy Singer, Thomas Kurome, Mayuko Kessler, Barbara Zakhartchenko, Valeri Wolf, Eckhard Weber, Felix Schnieke, Angelika Iglesias, Antonio |
| description | The safety of most human recombinant proteins can be evaluated in transgenic mice tolerant to specific human proteins. However, owing to insufficient genetic diversity and to fundamental differences in immune mechanisms, small-animal models of human diseases are often unsuitable for immunogenicity testing and for predicting adverse outcomes in human patients. Most human therapeutic antibodies trigger xenogeneic responses in wild-type animals and thus rapid clearance of the drugs, which makes in vivo toxicological testing of human antibodies challenging. Here we report the generation of Göttingen minipigs carrying a mini-repertoire of human genes for the immunoglobulin heavy chains γ1 and γ4 and the immunoglobulin light chain κ. In line with observations in human patients, the genetically modified minipigs tolerated the clinically non-immunogenic IgG1κ-isotype monoclonal antibodies daratumumab and bevacizumab, and elicited antibodies against the checkpoint inhibitor atezolizumab and the engineered interleukin cergutuzumab amunaleukin. The humanized minipigs can facilitate the safety and efficacy testing of therapeutic antibodies.
Göttingen minipigs genetically engineered to carry a mini-repertoire of human genes for immunoglobulin antibodies allow for the toxicological testing of human recombinant antibodies. |
| doi_str_mv | 10.1038/s41551-022-00921-2 |
| format | Article |
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Göttingen minipigs genetically engineered to carry a mini-repertoire of human genes for immunoglobulin antibodies allow for the toxicological testing of human recombinant antibodies.</description><identifier>ISSN: 2157-846X</identifier><identifier>EISSN: 2157-846X</identifier><identifier>DOI: 10.1038/s41551-022-00921-2</identifier><identifier>PMID: 36138193</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>38/1 ; 38/109 ; 38/22 ; 38/44 ; 38/77 ; 38/79 ; 38/91 ; 631/250/251/1567 ; 692/308/575 ; 82/80 ; Animal models ; Animals ; Antibodies ; Bevacizumab ; Biomedical and Life Sciences ; Biomedical Engineering/Biotechnology ; Biomedicine ; Chains ; Genes ; Genetic diversity ; Genetic engineering ; Genetic modification ; Humans ; Immune checkpoint ; Immune clearance ; Immunogenicity ; Immunoglobulin Heavy Chains - genetics ; Immunoglobulins ; Immunosuppressive agents ; In vivo methods and tests ; Interleukins ; Mice ; Mice, Transgenic ; Monoclonal antibodies ; Proteins ; Recombinant Proteins ; Safety ; Swine ; Swine, Miniature ; Transgenic mice</subject><ispartof>Nature biomedical engineering, 2022-11, Vol.6 (11), p.1248-1256</ispartof><rights>The Author(s) 2022</rights><rights>2022. The Author(s).</rights><rights>The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-e013979443747f36e2161ce16140d9efadf9edc137d076aa3fc47b15ff973b533</citedby><cites>FETCH-LOGICAL-c474t-e013979443747f36e2161ce16140d9efadf9edc137d076aa3fc47b15ff973b533</cites><orcidid>0000-0003-0481-117X ; 0000-0002-5761-9635 ; 0000-0003-3367-5795</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41551-022-00921-2$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41551-022-00921-2$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36138193$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Flisikowska, Tatiana</creatorcontrib><creatorcontrib>Egli, Jerome</creatorcontrib><creatorcontrib>Flisikowski, Krzysztof</creatorcontrib><creatorcontrib>Stumbaum, Marlene</creatorcontrib><creatorcontrib>Küng, Erich</creatorcontrib><creatorcontrib>Ebeling, Martin</creatorcontrib><creatorcontrib>Schmucki, Roland</creatorcontrib><creatorcontrib>Georges, Guy</creatorcontrib><creatorcontrib>Singer, Thomas</creatorcontrib><creatorcontrib>Kurome, Mayuko</creatorcontrib><creatorcontrib>Kessler, Barbara</creatorcontrib><creatorcontrib>Zakhartchenko, Valeri</creatorcontrib><creatorcontrib>Wolf, Eckhard</creatorcontrib><creatorcontrib>Weber, Felix</creatorcontrib><creatorcontrib>Schnieke, Angelika</creatorcontrib><creatorcontrib>Iglesias, Antonio</creatorcontrib><title>A humanized minipig model for the toxicological testing of therapeutic recombinant antibodies</title><title>Nature biomedical engineering</title><addtitle>Nat. Biomed. Eng</addtitle><addtitle>Nat Biomed Eng</addtitle><description>The safety of most human recombinant proteins can be evaluated in transgenic mice tolerant to specific human proteins. However, owing to insufficient genetic diversity and to fundamental differences in immune mechanisms, small-animal models of human diseases are often unsuitable for immunogenicity testing and for predicting adverse outcomes in human patients. Most human therapeutic antibodies trigger xenogeneic responses in wild-type animals and thus rapid clearance of the drugs, which makes in vivo toxicological testing of human antibodies challenging. Here we report the generation of Göttingen minipigs carrying a mini-repertoire of human genes for the immunoglobulin heavy chains γ1 and γ4 and the immunoglobulin light chain κ. In line with observations in human patients, the genetically modified minipigs tolerated the clinically non-immunogenic IgG1κ-isotype monoclonal antibodies daratumumab and bevacizumab, and elicited antibodies against the checkpoint inhibitor atezolizumab and the engineered interleukin cergutuzumab amunaleukin. The humanized minipigs can facilitate the safety and efficacy testing of therapeutic antibodies.
Göttingen minipigs genetically engineered to carry a mini-repertoire of human genes for immunoglobulin antibodies allow for the toxicological testing of human recombinant antibodies.</description><subject>38/1</subject><subject>38/109</subject><subject>38/22</subject><subject>38/44</subject><subject>38/77</subject><subject>38/79</subject><subject>38/91</subject><subject>631/250/251/1567</subject><subject>692/308/575</subject><subject>82/80</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Bevacizumab</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>Biomedicine</subject><subject>Chains</subject><subject>Genes</subject><subject>Genetic diversity</subject><subject>Genetic engineering</subject><subject>Genetic modification</subject><subject>Humans</subject><subject>Immune checkpoint</subject><subject>Immune clearance</subject><subject>Immunogenicity</subject><subject>Immunoglobulin Heavy Chains - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature biomedical engineering</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flisikowska, Tatiana</au><au>Egli, Jerome</au><au>Flisikowski, Krzysztof</au><au>Stumbaum, Marlene</au><au>Küng, Erich</au><au>Ebeling, Martin</au><au>Schmucki, Roland</au><au>Georges, Guy</au><au>Singer, Thomas</au><au>Kurome, Mayuko</au><au>Kessler, Barbara</au><au>Zakhartchenko, Valeri</au><au>Wolf, Eckhard</au><au>Weber, Felix</au><au>Schnieke, Angelika</au><au>Iglesias, Antonio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A humanized minipig model for the toxicological testing of therapeutic recombinant antibodies</atitle><jtitle>Nature biomedical engineering</jtitle><stitle>Nat. Biomed. Eng</stitle><addtitle>Nat Biomed Eng</addtitle><date>2022-11-01</date><risdate>2022</risdate><volume>6</volume><issue>11</issue><spage>1248</spage><epage>1256</epage><pages>1248-1256</pages><issn>2157-846X</issn><eissn>2157-846X</eissn><abstract>The safety of most human recombinant proteins can be evaluated in transgenic mice tolerant to specific human proteins. However, owing to insufficient genetic diversity and to fundamental differences in immune mechanisms, small-animal models of human diseases are often unsuitable for immunogenicity testing and for predicting adverse outcomes in human patients. Most human therapeutic antibodies trigger xenogeneic responses in wild-type animals and thus rapid clearance of the drugs, which makes in vivo toxicological testing of human antibodies challenging. Here we report the generation of Göttingen minipigs carrying a mini-repertoire of human genes for the immunoglobulin heavy chains γ1 and γ4 and the immunoglobulin light chain κ. In line with observations in human patients, the genetically modified minipigs tolerated the clinically non-immunogenic IgG1κ-isotype monoclonal antibodies daratumumab and bevacizumab, and elicited antibodies against the checkpoint inhibitor atezolizumab and the engineered interleukin cergutuzumab amunaleukin. The humanized minipigs can facilitate the safety and efficacy testing of therapeutic antibodies.
Göttingen minipigs genetically engineered to carry a mini-repertoire of human genes for immunoglobulin antibodies allow for the toxicological testing of human recombinant antibodies.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>36138193</pmid><doi>10.1038/s41551-022-00921-2</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-0481-117X</orcidid><orcidid>https://orcid.org/0000-0002-5761-9635</orcidid><orcidid>https://orcid.org/0000-0003-3367-5795</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 38/1 38/109 38/22 38/44 38/77 38/79 38/91 631/250/251/1567 692/308/575 82/80 Animal models Animals Antibodies Bevacizumab Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Chains Genes Genetic diversity Genetic engineering Genetic modification Humans Immune checkpoint Immune clearance Immunogenicity Immunoglobulin Heavy Chains - genetics Immunoglobulins Immunosuppressive agents In vivo methods and tests Interleukins Mice Mice, Transgenic Monoclonal antibodies Proteins Recombinant Proteins Safety Swine Swine, Miniature Transgenic mice |
| title | A humanized minipig model for the toxicological testing of therapeutic recombinant antibodies |
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