Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation
Abstract IgGs have become successful drug scaffolds by combining specific target binding with the ability to induce cellular cytotoxicity. Furthermore, IgGs possess unusually long half-lives in the blood (2-3 weeks). IgGs achieve such extraordinary half-lives through a pH-dependent interaction with...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-06-01
|
| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08252-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850100612837933056 |
|---|---|
| author | Esben Trabjerg Jeannette Nilsen Torleif Tollefsrud Gjølberg Jan Terje Andersen Alexander Leitner Kasper D. Rand |
| author_facet | Esben Trabjerg Jeannette Nilsen Torleif Tollefsrud Gjølberg Jan Terje Andersen Alexander Leitner Kasper D. Rand |
| author_sort | Esben Trabjerg |
| collection | DOAJ |
| description | Abstract IgGs have become successful drug scaffolds by combining specific target binding with the ability to induce cellular cytotoxicity. Furthermore, IgGs possess unusually long half-lives in the blood (2-3 weeks). IgGs achieve such extraordinary half-lives through a pH-dependent interaction with the FcRn-receptor whereby IgGs are recycled. No high-resolution structure of FcRn in complex with a full-length IgG is available, and the interaction was long thought to be mediated solely via the IgG-Fc. However, some IgGs with identical Fc-parts, but different Fab-domains, exhibit different half-lives, suggesting involvement of the Fab-domains in FcRn binding. Here, we employ structural mass spectrometry (HDX-MS and XL-MS) to explore the interaction of full-length IgGs with FcRn. HDX-MS and XL-MS experiments confirm an interaction between FcRn and the Fc-region of IgGs, through three cross-links between FcRn and the IgG-Fc-domain and a reduction in HDX in both the receptor and the Fc-region upon complex formation. However, FcRn-induced changes in HDX are also observed in the Fab-domains, supported by cross-links between the Fab-domains and the α3-domain of FcRn. Our results thus provide direct evidence for an IgG Fab-FcRn interaction. We envision that these results could advance the engineering of IgG-antibodies with tailored pharmacokinetics and enhanced efficacy. |
| format | Article |
| id | doaj-art-99ad3af7df854462ac549e6b3ff77aa3 |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-99ad3af7df854462ac549e6b3ff77aa32025-08-20T02:40:15ZengNature PortfolioCommunications Biology2399-36422025-06-018111310.1038/s42003-025-08252-zIdentification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formationEsben Trabjerg0Jeannette Nilsen1Torleif Tollefsrud Gjølberg2Jan Terje Andersen3Alexander Leitner4Kasper D. Rand5Department of Biology, Institute of Molecular Systems Biology, ETH ZürichPrecision Immunotherapy Alliance (PRIMA), University of OsloPrecision Immunotherapy Alliance (PRIMA), University of OsloPrecision Immunotherapy Alliance (PRIMA), University of OsloDepartment of Biology, Institute of Molecular Systems Biology, ETH ZürichDepartment of Pharmacy, University of CopenhagenAbstract IgGs have become successful drug scaffolds by combining specific target binding with the ability to induce cellular cytotoxicity. Furthermore, IgGs possess unusually long half-lives in the blood (2-3 weeks). IgGs achieve such extraordinary half-lives through a pH-dependent interaction with the FcRn-receptor whereby IgGs are recycled. No high-resolution structure of FcRn in complex with a full-length IgG is available, and the interaction was long thought to be mediated solely via the IgG-Fc. However, some IgGs with identical Fc-parts, but different Fab-domains, exhibit different half-lives, suggesting involvement of the Fab-domains in FcRn binding. Here, we employ structural mass spectrometry (HDX-MS and XL-MS) to explore the interaction of full-length IgGs with FcRn. HDX-MS and XL-MS experiments confirm an interaction between FcRn and the Fc-region of IgGs, through three cross-links between FcRn and the IgG-Fc-domain and a reduction in HDX in both the receptor and the Fc-region upon complex formation. However, FcRn-induced changes in HDX are also observed in the Fab-domains, supported by cross-links between the Fab-domains and the α3-domain of FcRn. Our results thus provide direct evidence for an IgG Fab-FcRn interaction. We envision that these results could advance the engineering of IgG-antibodies with tailored pharmacokinetics and enhanced efficacy.https://doi.org/10.1038/s42003-025-08252-z |
| spellingShingle | Esben Trabjerg Jeannette Nilsen Torleif Tollefsrud Gjølberg Jan Terje Andersen Alexander Leitner Kasper D. Rand Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation Communications Biology |
| title | Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation |
| title_full | Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation |
| title_fullStr | Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation |
| title_full_unstemmed | Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation |
| title_short | Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation |
| title_sort | identification of a direct interaction between the fab domains of igg antibodies and human fcrn upon igg fcrn complex formation |
| url | https://doi.org/10.1038/s42003-025-08252-z |
| work_keys_str_mv | AT esbentrabjerg identificationofadirectinteractionbetweenthefabdomainsofiggantibodiesandhumanfcrnuponiggfcrncomplexformation AT jeannettenilsen identificationofadirectinteractionbetweenthefabdomainsofiggantibodiesandhumanfcrnuponiggfcrncomplexformation AT torleiftollefsrudgjølberg identificationofadirectinteractionbetweenthefabdomainsofiggantibodiesandhumanfcrnuponiggfcrncomplexformation AT janterjeandersen identificationofadirectinteractionbetweenthefabdomainsofiggantibodiesandhumanfcrnuponiggfcrncomplexformation AT alexanderleitner identificationofadirectinteractionbetweenthefabdomainsofiggantibodiesandhumanfcrnuponiggfcrncomplexformation AT kasperdrand identificationofadirectinteractionbetweenthefabdomainsofiggantibodiesandhumanfcrnuponiggfcrncomplexformation |