Affinity Maturation Enhances Antibody Specificity but Compromises Conformational Stability
Summary: Monoclonal antibodies (mAbs) have recently emerged as one of the most promising classes of biotherapeutics. A potential advantage of B cell-derived mAbs as therapeutic agents is that they have been subjected to natural filtering mechanisms, which may enrich for B cell receptors (BCRs) with...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719311040 |
| _version_ | 1818499222932029440 |
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| author | Laila Shehata Daniel P. Maurer Anna Z. Wec Asparouh Lilov Elizabeth Champney Tingwan Sun Kimberly Archambault Irina Burnina Heather Lynaugh Xiaoyong Zhi Yingda Xu Laura M. Walker |
| author_facet | Laila Shehata Daniel P. Maurer Anna Z. Wec Asparouh Lilov Elizabeth Champney Tingwan Sun Kimberly Archambault Irina Burnina Heather Lynaugh Xiaoyong Zhi Yingda Xu Laura M. Walker |
| author_sort | Laila Shehata |
| collection | DOAJ |
| description | Summary: Monoclonal antibodies (mAbs) have recently emerged as one of the most promising classes of biotherapeutics. A potential advantage of B cell-derived mAbs as therapeutic agents is that they have been subjected to natural filtering mechanisms, which may enrich for B cell receptors (BCRs) with favorable biophysical properties. Here, we evaluated 400 human mAbs for polyreactivity, hydrophobicity, and thermal stability using high-throughput screening assays. Overall, mAbs derived from memory B cells and long-lived plasma cells (LLPCs) display reduced levels of polyreactivity, hydrophobicity, and thermal stability compared with naive B cell-derived mAbs. Somatic hypermutation (SHM) is inversely associated with all three biophysical properties, as well as BCR expression levels. Finally, the developability profiles of the human B cell-derived mAbs are comparable with those observed for clinical mAbs, suggesting their high therapeutic potential. The results provide insight into the biophysical consequences of affinity maturation and have implications for therapeutic antibody engineering and development. : Shehata et al. analyze the biophysical properties of human antibodies derived from multiple B cell subsets and find that somatic hypermutation is associated with increased antibody specificity but diminished conformational stability. The results provide insight into the biophysical consequences of affinity maturation and have implications for antibody discovery and engineering. Keywords: B cells, monoclonal antibodies, developability, polyreactivity, hydrophobicity, conformational stability |
| first_indexed | 2024-12-10T20:26:31Z |
| format | Article |
| id | doaj.art-fd7608d185584ab3a6267b03c19f18e7 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T20:26:31Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-fd7608d185584ab3a6267b03c19f18e72022-12-22T01:34:50ZengElsevierCell Reports2211-12472019-09-01281333003308.e4Affinity Maturation Enhances Antibody Specificity but Compromises Conformational StabilityLaila Shehata0Daniel P. Maurer1Anna Z. Wec2Asparouh Lilov3Elizabeth Champney4Tingwan Sun5Kimberly Archambault6Irina Burnina7Heather Lynaugh8Xiaoyong Zhi9Yingda Xu10Laura M. Walker11Adimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USAAdimab, LLC, Lebanon, NH 03766, USA; Corresponding authorSummary: Monoclonal antibodies (mAbs) have recently emerged as one of the most promising classes of biotherapeutics. A potential advantage of B cell-derived mAbs as therapeutic agents is that they have been subjected to natural filtering mechanisms, which may enrich for B cell receptors (BCRs) with favorable biophysical properties. Here, we evaluated 400 human mAbs for polyreactivity, hydrophobicity, and thermal stability using high-throughput screening assays. Overall, mAbs derived from memory B cells and long-lived plasma cells (LLPCs) display reduced levels of polyreactivity, hydrophobicity, and thermal stability compared with naive B cell-derived mAbs. Somatic hypermutation (SHM) is inversely associated with all three biophysical properties, as well as BCR expression levels. Finally, the developability profiles of the human B cell-derived mAbs are comparable with those observed for clinical mAbs, suggesting their high therapeutic potential. The results provide insight into the biophysical consequences of affinity maturation and have implications for therapeutic antibody engineering and development. : Shehata et al. analyze the biophysical properties of human antibodies derived from multiple B cell subsets and find that somatic hypermutation is associated with increased antibody specificity but diminished conformational stability. The results provide insight into the biophysical consequences of affinity maturation and have implications for antibody discovery and engineering. Keywords: B cells, monoclonal antibodies, developability, polyreactivity, hydrophobicity, conformational stabilityhttp://www.sciencedirect.com/science/article/pii/S2211124719311040 |
| spellingShingle | Laila Shehata Daniel P. Maurer Anna Z. Wec Asparouh Lilov Elizabeth Champney Tingwan Sun Kimberly Archambault Irina Burnina Heather Lynaugh Xiaoyong Zhi Yingda Xu Laura M. Walker Affinity Maturation Enhances Antibody Specificity but Compromises Conformational Stability Cell Reports |
| title | Affinity Maturation Enhances Antibody Specificity but Compromises Conformational Stability |
| title_full | Affinity Maturation Enhances Antibody Specificity but Compromises Conformational Stability |
| title_fullStr | Affinity Maturation Enhances Antibody Specificity but Compromises Conformational Stability |
| title_full_unstemmed | Affinity Maturation Enhances Antibody Specificity but Compromises Conformational Stability |
| title_short | Affinity Maturation Enhances Antibody Specificity but Compromises Conformational Stability |
| title_sort | affinity maturation enhances antibody specificity but compromises conformational stability |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719311040 |
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