Kinetics of free and ligand-bound atacicept in human serum
BAFF (B cell activation factor of the TNF family/B lymphocyte stimulator, BLyS) and APRIL (a proliferation-inducing ligand) are targeted by atacicept, a decoy receptor consisting of the extracellular domain of TACI (transmembrane activator and calcium-modulator and cyclophilin (CAML) interactor) fus...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1035556/full |
| _version_ | 1798016423232012288 |
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| author | Mahya Eslami Daniela Willen Orestis Papasouliotis Sonia Schuepbach-Mallpell Laure Willen Olivier Donzé Özkan Yalkinoglu Pascal Schneider |
| author_facet | Mahya Eslami Daniela Willen Orestis Papasouliotis Sonia Schuepbach-Mallpell Laure Willen Olivier Donzé Özkan Yalkinoglu Pascal Schneider |
| author_sort | Mahya Eslami |
| collection | DOAJ |
| description | BAFF (B cell activation factor of the TNF family/B lymphocyte stimulator, BLyS) and APRIL (a proliferation-inducing ligand) are targeted by atacicept, a decoy receptor consisting of the extracellular domain of TACI (transmembrane activator and calcium-modulator and cyclophilin (CAML) interactor) fused to the Fc portion of human IgG1. The purpose of the study was to characterize free and ligand-bound atacicept in humans. Total and active atacicept in serum of healthy volunteers receiving a single dose of subcutaneous atacicept or in patients treated weekly for one year were measured by ELISA, Western blot, or cell-based assays. Pharmacokinetics of free and bound atacicept were predicted based on total atacicept ELISA results. Persistence of complexes of purified atacicept bound to recombinant ligands was also monitored in mice. Results show that unbound or active atacicept in human serum exceeded 0.1 µg/ml for one week post administration, or throughout a 1-year treatment with weekly administrations. After a single administration of atacicept, endogenous BAFF bound to atacicept was detected after 8 h then increased about 100-fold within 2 to 4 weeks. Endogenous heteromers of BAFF and APRIL bound to atacicept also accumulated, but atacicept-APRIL complexes were not detected. In mice receiving intravenous injections of purified complexes pre-formed in vitro, atacicept-BAFF persisted longer (more than a week) than atacicept-APRIL (less than a day). Thus, only biologically inactive BAFF and BAFF-APRIL heteromers accumulate on atacicept in vivo. The measure of active atacicept provides further support for the once-weekly dosing regimen implemented in the clinical development of atacicept. |
| first_indexed | 2024-04-11T15:49:20Z |
| format | Article |
| id | doaj.art-9e52c1302a504221b6764fbf467e5860 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T15:49:20Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9e52c1302a504221b6764fbf467e58602022-12-22T04:15:23ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-12-011310.3389/fimmu.2022.10355561035556Kinetics of free and ligand-bound atacicept in human serumMahya Eslami0Daniela Willen1Orestis Papasouliotis2Sonia Schuepbach-Mallpell3Laure Willen4Olivier Donzé5Özkan Yalkinoglu6Pascal Schneider7Department of Immunobiology, University of Lausanne, Epalinges, SwitzerlandClinical Pharmacology, Translational Medicine, Merck Healthcare KGaA, Darmstadt, GermanyTranslational Medicine, Merck Institute for Pharmacometrics (an affiliate of Merck KGaA), Lausanne, SwitzerlandDepartment of Immunobiology, University of Lausanne, Epalinges, SwitzerlandDepartment of Immunobiology, University of Lausanne, Epalinges, SwitzerlandAdipogen Life Sciences, Epalinges, SwitzerlandClinical Pharmacology, Translational Medicine, Merck Healthcare KGaA, Darmstadt, GermanyDepartment of Immunobiology, University of Lausanne, Epalinges, SwitzerlandBAFF (B cell activation factor of the TNF family/B lymphocyte stimulator, BLyS) and APRIL (a proliferation-inducing ligand) are targeted by atacicept, a decoy receptor consisting of the extracellular domain of TACI (transmembrane activator and calcium-modulator and cyclophilin (CAML) interactor) fused to the Fc portion of human IgG1. The purpose of the study was to characterize free and ligand-bound atacicept in humans. Total and active atacicept in serum of healthy volunteers receiving a single dose of subcutaneous atacicept or in patients treated weekly for one year were measured by ELISA, Western blot, or cell-based assays. Pharmacokinetics of free and bound atacicept were predicted based on total atacicept ELISA results. Persistence of complexes of purified atacicept bound to recombinant ligands was also monitored in mice. Results show that unbound or active atacicept in human serum exceeded 0.1 µg/ml for one week post administration, or throughout a 1-year treatment with weekly administrations. After a single administration of atacicept, endogenous BAFF bound to atacicept was detected after 8 h then increased about 100-fold within 2 to 4 weeks. Endogenous heteromers of BAFF and APRIL bound to atacicept also accumulated, but atacicept-APRIL complexes were not detected. In mice receiving intravenous injections of purified complexes pre-formed in vitro, atacicept-BAFF persisted longer (more than a week) than atacicept-APRIL (less than a day). Thus, only biologically inactive BAFF and BAFF-APRIL heteromers accumulate on atacicept in vivo. The measure of active atacicept provides further support for the once-weekly dosing regimen implemented in the clinical development of atacicept.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1035556/fullBAFFAPRILheteromersreporter cellsatacicept |
| spellingShingle | Mahya Eslami Daniela Willen Orestis Papasouliotis Sonia Schuepbach-Mallpell Laure Willen Olivier Donzé Özkan Yalkinoglu Pascal Schneider Kinetics of free and ligand-bound atacicept in human serum Frontiers in Immunology BAFF APRIL heteromers reporter cells atacicept |
| title | Kinetics of free and ligand-bound atacicept in human serum |
| title_full | Kinetics of free and ligand-bound atacicept in human serum |
| title_fullStr | Kinetics of free and ligand-bound atacicept in human serum |
| title_full_unstemmed | Kinetics of free and ligand-bound atacicept in human serum |
| title_short | Kinetics of free and ligand-bound atacicept in human serum |
| title_sort | kinetics of free and ligand bound atacicept in human serum |
| topic | BAFF APRIL heteromers reporter cells atacicept |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1035556/full |
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