PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome
APS is an autoimmune disease in which antiphospholipid antibodies (aPL) cause vascular thrombosis and pregnancy morbidity. In patients with APS, aPL exert pathogenic actions by binding serum beta-2-glycoprotein I (β2GPI) via its N-terminal domain I (DI). We previously showed that bacterially-express...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02413/full |
| _version_ | 1818537130049142784 |
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| author | Thomas C. R. McDonnell Rohan Willis Charis Pericleous Vera M. Ripoll Ian P. Giles David. A. Isenberg David. A. Isenberg Allan R. Brasier Emilio B. Gonzalez Elizabeth Papalardo Zurina Romay-Penabad Mohammad Jamaluddin Yiannis Ioannou Yiannis Ioannou Anisur Rahman |
| author_facet | Thomas C. R. McDonnell Rohan Willis Charis Pericleous Vera M. Ripoll Ian P. Giles David. A. Isenberg David. A. Isenberg Allan R. Brasier Emilio B. Gonzalez Elizabeth Papalardo Zurina Romay-Penabad Mohammad Jamaluddin Yiannis Ioannou Yiannis Ioannou Anisur Rahman |
| author_sort | Thomas C. R. McDonnell |
| collection | DOAJ |
| description | APS is an autoimmune disease in which antiphospholipid antibodies (aPL) cause vascular thrombosis and pregnancy morbidity. In patients with APS, aPL exert pathogenic actions by binding serum beta-2-glycoprotein I (β2GPI) via its N-terminal domain I (DI). We previously showed that bacterially-expressed recombinant DI inhibits biological actions of IgG derived from serum of patients with APS (APS-IgG). DI is too small (7 kDa) to be a viable therapeutic agent. Addition of polyethylene glycol (PEGylation) to small molecules enhances the serum half-life, reduces proteolytic targeting and can decrease immunogenicity. It is a common method of tailoring pharmacokinetic parameters and has been used in the production of many therapies in the clinic. However, PEGylation of molecules may reduce their biological activity, and the size of the PEG group can alter the balance between activity and half-life extension. Here we achieve production of site-specific PEGylation of recombinant DI (PEG-DI) and describe the activities in vitro and in vivo of three variants with different size PEG groups. All variants were able to inhibit APS-IgG from: binding to whole β2GPI in ELISA, altering the clotting properties of human plasma and promoting thrombosis and tissue factor expression in mice. These findings provide an important step on the path to developing DI into a first-in-class therapeutic in APS. |
| first_indexed | 2024-12-11T18:46:47Z |
| format | Article |
| id | doaj.art-5dbe595d033240e5b72049f6a3eda9b1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T18:46:47Z |
| publishDate | 2018-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5dbe595d033240e5b72049f6a3eda9b12022-12-22T00:54:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-10-01910.3389/fimmu.2018.02413410734PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid SyndromeThomas C. R. McDonnell0Rohan Willis1Charis Pericleous2Vera M. Ripoll3Ian P. Giles4David. A. Isenberg5David. A. Isenberg6Allan R. Brasier7Emilio B. Gonzalez8Elizabeth Papalardo9Zurina Romay-Penabad10Mohammad Jamaluddin11Yiannis Ioannou12Yiannis Ioannou13Anisur Rahman14Division of Medicine, Centre for Rheumatology Research, University College London, London, United KingdomInternal Medicine, University of Texas Medical Branch, Galveston, TX, United StatesDivision of Medicine, Centre for Rheumatology Research, University College London, London, United KingdomDivision of Medicine, Centre for Rheumatology Research, University College London, London, United KingdomDivision of Medicine, Centre for Rheumatology Research, University College London, London, United KingdomDivision of Medicine, Centre for Rheumatology Research, University College London, London, United KingdomArthritis Research UK Centre for Adolescent Rheumatology, UCL/UCLH/Great Ormond Street Hospital, London, United KingdomInternal Medicine, University of Texas Medical Branch, Galveston, TX, United StatesInternal Medicine, University of Texas Medical Branch, Galveston, TX, United StatesInternal Medicine, University of Texas Medical Branch, Galveston, TX, United StatesInternal Medicine, University of Texas Medical Branch, Galveston, TX, United StatesInternal Medicine, University of Texas Medical Branch, Galveston, TX, United StatesDivision of Medicine, Centre for Rheumatology Research, University College London, London, United KingdomArthritis Research UK Centre for Adolescent Rheumatology, UCL/UCLH/Great Ormond Street Hospital, London, United KingdomDivision of Medicine, Centre for Rheumatology Research, University College London, London, United KingdomAPS is an autoimmune disease in which antiphospholipid antibodies (aPL) cause vascular thrombosis and pregnancy morbidity. In patients with APS, aPL exert pathogenic actions by binding serum beta-2-glycoprotein I (β2GPI) via its N-terminal domain I (DI). We previously showed that bacterially-expressed recombinant DI inhibits biological actions of IgG derived from serum of patients with APS (APS-IgG). DI is too small (7 kDa) to be a viable therapeutic agent. Addition of polyethylene glycol (PEGylation) to small molecules enhances the serum half-life, reduces proteolytic targeting and can decrease immunogenicity. It is a common method of tailoring pharmacokinetic parameters and has been used in the production of many therapies in the clinic. However, PEGylation of molecules may reduce their biological activity, and the size of the PEG group can alter the balance between activity and half-life extension. Here we achieve production of site-specific PEGylation of recombinant DI (PEG-DI) and describe the activities in vitro and in vivo of three variants with different size PEG groups. All variants were able to inhibit APS-IgG from: binding to whole β2GPI in ELISA, altering the clotting properties of human plasma and promoting thrombosis and tissue factor expression in mice. These findings provide an important step on the path to developing DI into a first-in-class therapeutic in APS.https://www.frontiersin.org/article/10.3389/fimmu.2018.02413/fullantiphospholipid syndromePEGylationdomain Itherapeuticsbiologics |
| spellingShingle | Thomas C. R. McDonnell Rohan Willis Charis Pericleous Vera M. Ripoll Ian P. Giles David. A. Isenberg David. A. Isenberg Allan R. Brasier Emilio B. Gonzalez Elizabeth Papalardo Zurina Romay-Penabad Mohammad Jamaluddin Yiannis Ioannou Yiannis Ioannou Anisur Rahman PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome Frontiers in Immunology antiphospholipid syndrome PEGylation domain I therapeutics biologics |
| title | PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome |
| title_full | PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome |
| title_fullStr | PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome |
| title_full_unstemmed | PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome |
| title_short | PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome |
| title_sort | pegylated domain i of beta 2 glycoprotein i inhibits the binding coagulopathic and thrombogenic properties of igg from patients with the antiphospholipid syndrome |
| topic | antiphospholipid syndrome PEGylation domain I therapeutics biologics |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02413/full |
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