Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics
An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation,...
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| creator | Joubert, Marisa K Deshpande, Meghana Yang, Jane Reynolds, Helen Bryson, Christine Fogg, Mark Baker, Matthew P Herskovitz, Jonathan Goletz, Theresa J Zhou, Lei Moxness, Michael Flynn, Gregory C Narhi, Linda O Jawa, Vibha |
| description | An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-γ secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed. |
| doi_str_mv | 10.1371/journal.pone.0159328 |
| format | Article |
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Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-γ secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0159328</identifier><identifier>PMID: 27494246</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antibodies, Monoclonal - genetics ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - metabolism ; Antigens ; Assaying ; Biological products ; Biology and Life Sciences ; Biosimilar Pharmaceuticals ; Cell Proliferation ; Cells, Cultured ; Cytokines ; Cytokines - analysis ; Dendritic cells ; Engineering and Technology ; Enzyme-Linked Immunosorbent Assay ; Enzyme-Linked Immunospot Assay ; Enzymes ; Galactose ; Glycosylation ; Health aspects ; Humans ; Immunogenetics ; Immunogenicity ; Immunoglobulins ; Immunology ; Interferon ; Interferon-gamma - analysis ; Interleukin 2 ; Interleukin-2 - analysis ; Leukocytes (mononuclear) ; Leukocytes, Mononuclear - cytology ; Leukocytes, Mononuclear - immunology ; Leukocytes, Mononuclear - metabolism ; Life span ; Lymphocyte Activation ; Lymphocytes T ; Mannose ; Medicine and Health Sciences ; Monoclonal antibodies ; Mutation ; Peripheral blood mononuclear cells ; Point Mutation ; Product development ; Product quality ; Proteins ; Research and Analysis Methods ; Risk Assessment ; Rodents ; Signal transduction ; Stirring ; Sugar ; T cell receptors ; T-Lymphocytes - cytology ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; γ-Interferon</subject><ispartof>PloS one, 2016-08, Vol.11 (8), p.e0159328-e0159328</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Joubert 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>2016 Joubert et al 2016 Joubert et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c791t-58efe7889b4b300b37f6a33bfe5f909c7e8c189af8bbaa233a43a3936c9c12bc3</citedby><cites>FETCH-LOGICAL-c791t-58efe7889b4b300b37f6a33bfe5f909c7e8c189af8bbaa233a43a3936c9c12bc3</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/PMC4975389/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975389/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27494246$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Stoddart, Cheryl A.</contributor><creatorcontrib>Joubert, Marisa K</creatorcontrib><creatorcontrib>Deshpande, Meghana</creatorcontrib><creatorcontrib>Yang, Jane</creatorcontrib><creatorcontrib>Reynolds, Helen</creatorcontrib><creatorcontrib>Bryson, Christine</creatorcontrib><creatorcontrib>Fogg, Mark</creatorcontrib><creatorcontrib>Baker, Matthew P</creatorcontrib><creatorcontrib>Herskovitz, Jonathan</creatorcontrib><creatorcontrib>Goletz, Theresa J</creatorcontrib><creatorcontrib>Zhou, Lei</creatorcontrib><creatorcontrib>Moxness, Michael</creatorcontrib><creatorcontrib>Flynn, Gregory C</creatorcontrib><creatorcontrib>Narhi, Linda O</creatorcontrib><creatorcontrib>Jawa, Vibha</creatorcontrib><title>Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-γ secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed.</description><subject>Antibodies, Monoclonal - genetics</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - metabolism</subject><subject>Antigens</subject><subject>Assaying</subject><subject>Biological products</subject><subject>Biology and Life Sciences</subject><subject>Biosimilar Pharmaceuticals</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Cytokines</subject><subject>Cytokines - analysis</subject><subject>Dendritic cells</subject><subject>Engineering and Technology</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Enzyme-Linked Immunospot Assay</subject><subject>Enzymes</subject><subject>Galactose</subject><subject>Glycosylation</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immunogenetics</subject><subject>Immunogenicity</subject><subject>Immunoglobulins</subject><subject>Immunology</subject><subject>Interferon</subject><subject>Interferon-gamma - 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cytology</topic><topic>Leukocytes, Mononuclear - immunology</topic><topic>Leukocytes, Mononuclear - metabolism</topic><topic>Life span</topic><topic>Lymphocyte Activation</topic><topic>Lymphocytes T</topic><topic>Mannose</topic><topic>Medicine and Health Sciences</topic><topic>Monoclonal antibodies</topic><topic>Mutation</topic><topic>Peripheral blood mononuclear cells</topic><topic>Point Mutation</topic><topic>Product development</topic><topic>Product quality</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>Risk Assessment</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Stirring</topic><topic>Sugar</topic><topic>T cell receptors</topic><topic>T-Lymphocytes - cytology</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Joubert, Marisa K</creatorcontrib><creatorcontrib>Deshpande, Meghana</creatorcontrib><creatorcontrib>Yang, Jane</creatorcontrib><creatorcontrib>Reynolds, Helen</creatorcontrib><creatorcontrib>Bryson, Christine</creatorcontrib><creatorcontrib>Fogg, Mark</creatorcontrib><creatorcontrib>Baker, Matthew P</creatorcontrib><creatorcontrib>Herskovitz, Jonathan</creatorcontrib><creatorcontrib>Goletz, Theresa J</creatorcontrib><creatorcontrib>Zhou, Lei</creatorcontrib><creatorcontrib>Moxness, Michael</creatorcontrib><creatorcontrib>Flynn, Gregory C</creatorcontrib><creatorcontrib>Narhi, Linda O</creatorcontrib><creatorcontrib>Jawa, Vibha</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Proquest Nursing & Allied Health Source</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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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>Joubert, Marisa K</au><au>Deshpande, Meghana</au><au>Yang, Jane</au><au>Reynolds, Helen</au><au>Bryson, Christine</au><au>Fogg, Mark</au><au>Baker, Matthew P</au><au>Herskovitz, Jonathan</au><au>Goletz, Theresa J</au><au>Zhou, Lei</au><au>Moxness, Michael</au><au>Flynn, Gregory C</au><au>Narhi, Linda O</au><au>Jawa, Vibha</au><au>Stoddart, Cheryl A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-08-05</date><risdate>2016</risdate><volume>11</volume><issue>8</issue><spage>e0159328</spage><epage>e0159328</epage><pages>e0159328-e0159328</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-γ secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27494246</pmid><doi>10.1371/journal.pone.0159328</doi><tpages>e0159328</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-08, Vol.11 (8), p.e0159328-e0159328 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1812517337 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Antibodies, Monoclonal - genetics Antibodies, Monoclonal - immunology Antibodies, Monoclonal - metabolism Antigens Assaying Biological products Biology and Life Sciences Biosimilar Pharmaceuticals Cell Proliferation Cells, Cultured Cytokines Cytokines - analysis Dendritic cells Engineering and Technology Enzyme-Linked Immunosorbent Assay Enzyme-Linked Immunospot Assay Enzymes Galactose Glycosylation Health aspects Humans Immunogenetics Immunogenicity Immunoglobulins Immunology Interferon Interferon-gamma - analysis Interleukin 2 Interleukin-2 - analysis Leukocytes (mononuclear) Leukocytes, Mononuclear - cytology Leukocytes, Mononuclear - immunology Leukocytes, Mononuclear - metabolism Life span Lymphocyte Activation Lymphocytes T Mannose Medicine and Health Sciences Monoclonal antibodies Mutation Peripheral blood mononuclear cells Point Mutation Product development Product quality Proteins Research and Analysis Methods Risk Assessment Rodents Signal transduction Stirring Sugar T cell receptors T-Lymphocytes - cytology T-Lymphocytes - immunology T-Lymphocytes - metabolism γ-Interferon |
| title | Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics |
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