Discovery of potent allosteric antibodies inhibiting EGFR
In this work, we report the discovery of potent anti-epidermal growth factor receptor (EGFR) allosteric heavy-chain antibodies by combining camelid immunization and fluorescence-activated cell sorting (FACS). After immunization and yeast surface display library construction, allosteric clones were o...
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| Format: | Article |
| Language: | English |
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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/10.1080/19420862.2024.2406548 |
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| author | Léxane Fournier Lukas Pekar Birgitta Leuthner Harald Kolmar Lars Toleikis Stefan Becker |
| author_facet | Léxane Fournier Lukas Pekar Birgitta Leuthner Harald Kolmar Lars Toleikis Stefan Becker |
| author_sort | Léxane Fournier |
| collection | DOAJ |
| description | In this work, we report the discovery of potent anti-epidermal growth factor receptor (EGFR) allosteric heavy-chain antibodies by combining camelid immunization and fluorescence-activated cell sorting (FACS). After immunization and yeast surface display library construction, allosteric clones were obtained by introducing the labeled EGF Fc fusion protein as an additional criterion for FACS. This sorting method enabled the identification of 11 heavy-chain antibodies that did not compete with the orthosteric ligand EGF for the binding to EGFR. These antibodies bind to a triple-negative breast cancer cell line expressing EGFR with affinities in the picomolar to nanomolar range. Those camelid-derived antibodies also exhibit interesting properties by modulating EGFR affinity for EGF. Moreover, they are also able to inhibit EGF-induced downstream signaling pathways. In particular, we identified one clone that is more potent than the approved blocking antibody cetuximab in inhibiting both PI3K/AKT and MAPK/ERK pathways. Our results suggest that allosteric antibodies may be potential new modalities for therapeutics. |
| format | Article |
| id | doaj-art-47ecdc7002cb4c918adba46e3118162a |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-47ecdc7002cb4c918adba46e3118162a2025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2406548Discovery of potent allosteric antibodies inhibiting EGFRLéxane Fournier0Lukas Pekar1Birgitta Leuthner2Harald Kolmar3Lars Toleikis4Stefan Becker5Early Protein Supply and Characterization, Merck Healthcare KGaA, Darmstadt, GermanyAntibody Discovery and Protein Engineering, Merck Healthcare KGaA, Darmstadt, GermanyDiscovery Pharmacology, Merck Healthcare KGaA, Darmstadt, GermanyInstitute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Darmstadt, GermanyEarly Protein Supply and Characterization, Merck Healthcare KGaA, Darmstadt, GermanyEarly Protein Supply and Characterization, Merck Healthcare KGaA, Darmstadt, GermanyIn this work, we report the discovery of potent anti-epidermal growth factor receptor (EGFR) allosteric heavy-chain antibodies by combining camelid immunization and fluorescence-activated cell sorting (FACS). After immunization and yeast surface display library construction, allosteric clones were obtained by introducing the labeled EGF Fc fusion protein as an additional criterion for FACS. This sorting method enabled the identification of 11 heavy-chain antibodies that did not compete with the orthosteric ligand EGF for the binding to EGFR. These antibodies bind to a triple-negative breast cancer cell line expressing EGFR with affinities in the picomolar to nanomolar range. Those camelid-derived antibodies also exhibit interesting properties by modulating EGFR affinity for EGF. Moreover, they are also able to inhibit EGF-induced downstream signaling pathways. In particular, we identified one clone that is more potent than the approved blocking antibody cetuximab in inhibiting both PI3K/AKT and MAPK/ERK pathways. Our results suggest that allosteric antibodies may be potential new modalities for therapeutics.https://www.tandfonline.com/doi/10.1080/19420862.2024.2406548Allosteryantibody discoverycancer therapyEGFRheavy-chain antibodytriple-negative breast cancer |
| spellingShingle | Léxane Fournier Lukas Pekar Birgitta Leuthner Harald Kolmar Lars Toleikis Stefan Becker Discovery of potent allosteric antibodies inhibiting EGFR mAbs Allostery antibody discovery cancer therapy EGFR heavy-chain antibody triple-negative breast cancer |
| title | Discovery of potent allosteric antibodies inhibiting EGFR |
| title_full | Discovery of potent allosteric antibodies inhibiting EGFR |
| title_fullStr | Discovery of potent allosteric antibodies inhibiting EGFR |
| title_full_unstemmed | Discovery of potent allosteric antibodies inhibiting EGFR |
| title_short | Discovery of potent allosteric antibodies inhibiting EGFR |
| title_sort | discovery of potent allosteric antibodies inhibiting egfr |
| topic | Allostery antibody discovery cancer therapy EGFR heavy-chain antibody triple-negative breast cancer |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2406548 |
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