Insight into the avidity–affinity relationship of the bivalent, pH-dependent interaction between IgG and FcRn
Monoclonal antibodies (mAbs) as therapeutics necessitate favorable pharmacokinetic properties, including extended serum half-life, achieved through pH-dependent binding to the neonatal Fc receptor (FcRn). While prior research has mainly investigated IgG-FcRn binding kinetics with a focus on single a...
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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/10.1080/19420862.2024.2361585 |
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| author | Johannes Reusch Jan Terje Andersen Ulrich Rant Tilman Schlothauer |
| author_facet | Johannes Reusch Jan Terje Andersen Ulrich Rant Tilman Schlothauer |
| author_sort | Johannes Reusch |
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| description | Monoclonal antibodies (mAbs) as therapeutics necessitate favorable pharmacokinetic properties, including extended serum half-life, achieved through pH-dependent binding to the neonatal Fc receptor (FcRn). While prior research has mainly investigated IgG-FcRn binding kinetics with a focus on single affinity values, it has been shown that each IgG molecule can engage two FcRn molecules throughout an endosomal pH gradient. As such, we present here a more comprehensive analysis of these interactions with an emphasis on both affinity and avidity by taking advantage of switchSENSE technology, a surface-based biosensor where recombinant FcRn was immobilized via short DNA nanolevers, mimicking the membranous orientation of the receptor. The results revealed insight into the avidity-to-affinity relationship, where assessing binding through a pH gradient ranging from pH 5.8 to 7.4 showed that the half-life extended IgG1-YTE has an affinity inflection point at pH 7.2, reflecting its engineering for improved FcRn binding compared with the wild-type counterpart. Furthermore, IgG1-YTE displayed a pH switch for the avidity enhancement factor at pH 6.2, reflecting strong receptor binding to both sides of the YTE-containing Fc, while avidity was abolished at pH 7.4. When compared with classical surface plasmon resonance (SPR) technology and complementary methods, the use of switchSENSE demonstrated superior capabilities in differentiating affinity from avidity within a single measurement. Thus, the methodology provides reliable kinetic rate parameters for both binding modes and their direct relationship as a function of pH. Also, it deciphers the potential effect of the variable Fab arms on FcRn binding, in which SPR has limitations. Our study offers guidance for how FcRn binding properties can be studied for IgG engineering strategies. |
| format | Article |
| id | doaj-art-8e21d7845285420f8c4d1cd91773b5b4 |
| 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-8e21d7845285420f8c4d1cd91773b5b42025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2361585Insight into the avidity–affinity relationship of the bivalent, pH-dependent interaction between IgG and FcRnJohannes Reusch0Jan Terje Andersen1Ulrich Rant2Tilman Schlothauer3Dynamic Biosensors GmbH, Munich, GermanyDepartment of Immunology, Oslo University Hospital Rikshospitalet, Oslo, NorwayDynamic Biosensors GmbH, Munich, GermanyRoche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, GermanyMonoclonal antibodies (mAbs) as therapeutics necessitate favorable pharmacokinetic properties, including extended serum half-life, achieved through pH-dependent binding to the neonatal Fc receptor (FcRn). While prior research has mainly investigated IgG-FcRn binding kinetics with a focus on single affinity values, it has been shown that each IgG molecule can engage two FcRn molecules throughout an endosomal pH gradient. As such, we present here a more comprehensive analysis of these interactions with an emphasis on both affinity and avidity by taking advantage of switchSENSE technology, a surface-based biosensor where recombinant FcRn was immobilized via short DNA nanolevers, mimicking the membranous orientation of the receptor. The results revealed insight into the avidity-to-affinity relationship, where assessing binding through a pH gradient ranging from pH 5.8 to 7.4 showed that the half-life extended IgG1-YTE has an affinity inflection point at pH 7.2, reflecting its engineering for improved FcRn binding compared with the wild-type counterpart. Furthermore, IgG1-YTE displayed a pH switch for the avidity enhancement factor at pH 6.2, reflecting strong receptor binding to both sides of the YTE-containing Fc, while avidity was abolished at pH 7.4. When compared with classical surface plasmon resonance (SPR) technology and complementary methods, the use of switchSENSE demonstrated superior capabilities in differentiating affinity from avidity within a single measurement. Thus, the methodology provides reliable kinetic rate parameters for both binding modes and their direct relationship as a function of pH. Also, it deciphers the potential effect of the variable Fab arms on FcRn binding, in which SPR has limitations. Our study offers guidance for how FcRn binding properties can be studied for IgG engineering strategies.https://www.tandfonline.com/doi/10.1080/19420862.2024.2361585Affinityaviditybinding kineticsbiosensorFcRnph dependency |
| spellingShingle | Johannes Reusch Jan Terje Andersen Ulrich Rant Tilman Schlothauer Insight into the avidity–affinity relationship of the bivalent, pH-dependent interaction between IgG and FcRn mAbs Affinity avidity binding kinetics biosensor FcRn ph dependency |
| title | Insight into the avidity–affinity relationship of the bivalent, pH-dependent interaction between IgG and FcRn |
| title_full | Insight into the avidity–affinity relationship of the bivalent, pH-dependent interaction between IgG and FcRn |
| title_fullStr | Insight into the avidity–affinity relationship of the bivalent, pH-dependent interaction between IgG and FcRn |
| title_full_unstemmed | Insight into the avidity–affinity relationship of the bivalent, pH-dependent interaction between IgG and FcRn |
| title_short | Insight into the avidity–affinity relationship of the bivalent, pH-dependent interaction between IgG and FcRn |
| title_sort | insight into the avidity affinity relationship of the bivalent ph dependent interaction between igg and fcrn |
| topic | Affinity avidity binding kinetics biosensor FcRn ph dependency |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2361585 |
| work_keys_str_mv | AT johannesreusch insightintotheavidityaffinityrelationshipofthebivalentphdependentinteractionbetweeniggandfcrn AT janterjeandersen insightintotheavidityaffinityrelationshipofthebivalentphdependentinteractionbetweeniggandfcrn AT ulrichrant insightintotheavidityaffinityrelationshipofthebivalentphdependentinteractionbetweeniggandfcrn AT tilmanschlothauer insightintotheavidityaffinityrelationshipofthebivalentphdependentinteractionbetweeniggandfcrn |