Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinity
Transgenic animals incorporating human antibody genes are extremely attractive for drug development because they obviate subsequent antibody humanization procedures required for therapeutic translation. Transgenic platforms have previously been established using mice, but also more recently rats, ch...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2020.1846900 |
| _version_ | 1818481376693846016 |
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| author | Francesca Ros Sonja Offner Stefan Klostermann Irmgard Thorey Helmut Niersbach Sebastian Breuer Grit Zarnt Stefan Lorenz Juergen Puels Basile Siewe Nicole Schueler Tajana Dragicevic Dominique Ostler Imke Hansen-Wester Valeria Lifke Brigitte Kaluza Klaus Kaluza Wim van Schooten Roland Buelow Alain C Tissot Josef Platzer |
| author_facet | Francesca Ros Sonja Offner Stefan Klostermann Irmgard Thorey Helmut Niersbach Sebastian Breuer Grit Zarnt Stefan Lorenz Juergen Puels Basile Siewe Nicole Schueler Tajana Dragicevic Dominique Ostler Imke Hansen-Wester Valeria Lifke Brigitte Kaluza Klaus Kaluza Wim van Schooten Roland Buelow Alain C Tissot Josef Platzer |
| author_sort | Francesca Ros |
| collection | DOAJ |
| description | Transgenic animals incorporating human antibody genes are extremely attractive for drug development because they obviate subsequent antibody humanization procedures required for therapeutic translation. Transgenic platforms have previously been established using mice, but also more recently rats, chickens, and cows and are now in abundant use for drug development. However, rabbit-based antibody generation, with a strong track record for specificity and affinity, is able to include gene conversion mediated sequence diversification, thereby enhancing binder maturation and improving the variance/selection of output antibodies in a different way than in rodents. Since it additionally frequently permits good binder generation against antigens that are only weakly immunogenic in other organisms, it is a highly interesting species for therapeutic antibody generation. We report here on the generation, utilization, and analysis of the first transgenic rabbit strain for human antibody production. Through the knockout of endogenous IgM genes and the introduction of human immunoglobulin sequences, this rabbit strain has been engineered to generate a highly diverse human IgG antibody repertoire. We further incorporated human CD79a/b and Bcl2 (B-cell lymphoma 2) genes, which enhance B-cell receptor expression and B-cell survival. Following immunization against the angiogenic factor BMP9 (Bone Morphogenetic Proteins 9), we were able to isolate a set of exquisitely affine and specific neutralizing antibodies from these rabbits. Sequence analysis of these binders revealed that both somatic hypermutation and gene conversion are fully operational in this strain, without compromising the very high degree of humanness. This powerful new transgenic strategy will allow further expansion of the use of endogenous immune mechanisms in drug development. |
| first_indexed | 2024-12-10T11:34:03Z |
| format | Article |
| id | doaj.art-eb4cfd37c8a244a096d64b9303c73a7f |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-12-10T11:34:03Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-eb4cfd37c8a244a096d64b9303c73a7f2022-12-22T01:50:29ZengTaylor & Francis GroupmAbs1942-08621942-08702020-01-0112110.1080/19420862.2020.1846900Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinityFrancesca Ros0Sonja Offner1Stefan Klostermann2Irmgard Thorey3Helmut Niersbach4Sebastian Breuer5Grit Zarnt6Stefan Lorenz7Juergen Puels8Basile Siewe9Nicole Schueler10Tajana Dragicevic11Dominique Ostler12Imke Hansen-Wester13Valeria Lifke14Brigitte Kaluza15Klaus Kaluza16Wim van Schooten17Roland Buelow18Alain C Tissot19Josef Platzer20Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Informatics, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyTÜV SÜD Product Service GmbH, Munich, GermanyTHE JACKSON LABORATORY JMCRS, Sacramento, CA, USARoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanySupplier Quality Management, Global External Quality Roche Diagnostics GmbH, Penzberg, GermanyPersonalized Healthcare Solution, Immunoassay Development and System Integration, Roche Diagnostics GmbH, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyTeneobio, Inc., Newark, CA, USATeneobio, Inc., Newark, CA, USARoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyTransgenic animals incorporating human antibody genes are extremely attractive for drug development because they obviate subsequent antibody humanization procedures required for therapeutic translation. Transgenic platforms have previously been established using mice, but also more recently rats, chickens, and cows and are now in abundant use for drug development. However, rabbit-based antibody generation, with a strong track record for specificity and affinity, is able to include gene conversion mediated sequence diversification, thereby enhancing binder maturation and improving the variance/selection of output antibodies in a different way than in rodents. Since it additionally frequently permits good binder generation against antigens that are only weakly immunogenic in other organisms, it is a highly interesting species for therapeutic antibody generation. We report here on the generation, utilization, and analysis of the first transgenic rabbit strain for human antibody production. Through the knockout of endogenous IgM genes and the introduction of human immunoglobulin sequences, this rabbit strain has been engineered to generate a highly diverse human IgG antibody repertoire. We further incorporated human CD79a/b and Bcl2 (B-cell lymphoma 2) genes, which enhance B-cell receptor expression and B-cell survival. Following immunization against the angiogenic factor BMP9 (Bone Morphogenetic Proteins 9), we were able to isolate a set of exquisitely affine and specific neutralizing antibodies from these rabbits. Sequence analysis of these binders revealed that both somatic hypermutation and gene conversion are fully operational in this strain, without compromising the very high degree of humanness. This powerful new transgenic strategy will allow further expansion of the use of endogenous immune mechanisms in drug development.https://www.tandfonline.com/doi/10.1080/19420862.2020.1846900Rabbithuman immunoglobulinsIgGtransgenicimmune repertoiregene conversion |
| spellingShingle | Francesca Ros Sonja Offner Stefan Klostermann Irmgard Thorey Helmut Niersbach Sebastian Breuer Grit Zarnt Stefan Lorenz Juergen Puels Basile Siewe Nicole Schueler Tajana Dragicevic Dominique Ostler Imke Hansen-Wester Valeria Lifke Brigitte Kaluza Klaus Kaluza Wim van Schooten Roland Buelow Alain C Tissot Josef Platzer Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinity mAbs Rabbit human immunoglobulins IgG transgenic immune repertoire gene conversion |
| title | Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinity |
| title_full | Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinity |
| title_fullStr | Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinity |
| title_full_unstemmed | Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinity |
| title_short | Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinity |
| title_sort | rabbits transgenic for human igg genes recapitulating rabbit b cell biology to generate human antibodies of high specificity and affinity |
| topic | Rabbit human immunoglobulins IgG transgenic immune repertoire gene conversion |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2020.1846900 |
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