Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies
Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have...
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2362789 |
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| author | Wen-Ting K. Tsai Yinyin Li Zhaojun Yin Peter Tran Qui Phung Zhenru Zhou Kun Peng Dan Qin Sien Tam Christoph Spiess Jochen Brumm Manda Wong Zhengmao Ye Patrick Wu Sivan Cohen Paul J. Carter |
| author_facet | Wen-Ting K. Tsai Yinyin Li Zhaojun Yin Peter Tran Qui Phung Zhenru Zhou Kun Peng Dan Qin Sien Tam Christoph Spiess Jochen Brumm Manda Wong Zhengmao Ye Patrick Wu Sivan Cohen Paul J. Carter |
| author_sort | Wen-Ting K. Tsai |
| collection | DOAJ |
| description | Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient in vivo assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG1 antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by in silico prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. In toto, these data suggest that the KIH mutations and in vitro assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG1, nor do the Fab mutations used for efficient in vivo assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG1 as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts. |
| format | Article |
| id | doaj-art-9805ef0547804dc680ba4370dfa5869f |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
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| series | mAbs |
| spelling | doaj-art-9805ef0547804dc680ba4370dfa5869f2025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2362789Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodiesWen-Ting K. Tsai0Yinyin Li1Zhaojun Yin2Peter Tran3Qui Phung4Zhenru Zhou5Kun Peng6Dan Qin7Sien Tam8Christoph Spiess9Jochen Brumm10Manda Wong11Zhengmao Ye12Patrick Wu13Sivan Cohen14Paul J. Carter15Department of Antibody Engineering, Genentech, Inc, South San Francisco, CA, USADepartment of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, CA, USADepartment of Bioanalytical Sciences, Genentech, Inc, South San Francisco, CA, USADepartment of Bioanalytical Sciences, Genentech, Inc, South San Francisco, CA, USADepartment of Microchemistry, Proteomics and Lipidomics, Genentech, Inc, South San Francisco, CA, USADepartment of Microchemistry, Proteomics and Lipidomics, Genentech, Inc, South San Francisco, CA, USADepartment of Bioanalytical Sciences, Genentech, Inc, South San Francisco, CA, USADepartment of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, CA, USADepartment of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, CA, USADepartment of Antibody Engineering, Genentech, Inc, South San Francisco, CA, USADepartment of Nonclinical Biostatistics, Genentech, Inc, South San Francisco, CA, USADepartment of Structural Biology, Genentech, Inc, South San Francisco, CA, USADepartment of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, CA, USADepartment of Bioanalytical Sciences, Genentech, Inc, South San Francisco, CA, USADepartment of Bioanalytical Sciences, Genentech, Inc, South San Francisco, CA, USADepartment of Antibody Engineering, Genentech, Inc, South San Francisco, CA, USABispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient in vivo assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG1 antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by in silico prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. In toto, these data suggest that the KIH mutations and in vitro assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG1, nor do the Fab mutations used for efficient in vivo assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG1 as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.https://www.tandfonline.com/doi/10.1080/19420862.2024.2362789Anti-drug antibodiesbispecific antibodyex vivo T cell assayimmunogenicityin silico predictionknobs-into-holes |
| spellingShingle | Wen-Ting K. Tsai Yinyin Li Zhaojun Yin Peter Tran Qui Phung Zhenru Zhou Kun Peng Dan Qin Sien Tam Christoph Spiess Jochen Brumm Manda Wong Zhengmao Ye Patrick Wu Sivan Cohen Paul J. Carter Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies mAbs Anti-drug antibodies bispecific antibody ex vivo T cell assay immunogenicity in silico prediction knobs-into-holes |
| title | Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies |
| title_full | Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies |
| title_fullStr | Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies |
| title_full_unstemmed | Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies |
| title_short | Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies |
| title_sort | nonclinical immunogenicity risk assessment for knobs into holes bispecific igg1 antibodies |
| topic | Anti-drug antibodies bispecific antibody ex vivo T cell assay immunogenicity in silico prediction knobs-into-holes |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2362789 |
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