GC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpura
Abstract Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening blood disorder characterized by the formation of blood clots in small blood vessels. It is caused by antibodies targeting the A disintegrin and metalloprotease with thrombospondin type 1 repeats, membe...
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-80674-x |
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| author | Heechun Kwak Gahee Choi Suyong Kim Ji-Min Park Youngeun Kwon Yongmin Lee Chaemok Lee Shangbin Yang Spero Cataland Sunghyun Kim Soo-Mee Bang Jae-Ho Yoon Wooin Lee Hyun-Ja Nam |
| author_facet | Heechun Kwak Gahee Choi Suyong Kim Ji-Min Park Youngeun Kwon Yongmin Lee Chaemok Lee Shangbin Yang Spero Cataland Sunghyun Kim Soo-Mee Bang Jae-Ho Yoon Wooin Lee Hyun-Ja Nam |
| author_sort | Heechun Kwak |
| collection | DOAJ |
| description | Abstract Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening blood disorder characterized by the formation of blood clots in small blood vessels. It is caused by antibodies targeting the A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13), which plays a role in cleaving von Willebrand factor. Most patients with iTTP have autoantibodies against specific domains of the ADAMTS13 protein, particularly the cysteine-rich and spacer domains. This study aimed to identify ADAMTS13 muteins that are resistant to autoantibodies and maintain their enzymatic activity. A panel of muteins was generated using rational and random mutagenesis methods and screened for autoantibody binding and ADAMTS13 activity. The selected muteins were assessed for pharmacodynamic biomarkers and pharmacokinetic profiles in the iTTP-mimic and wild-type mice, respectively. GC1126A was the most effective variant for escaping autoantibodies and had a longer half-life than the wild-type ADAMTS13 fragment (MDTCS). In the iTTP-mimic mouse model, GC1126A treatment significantly improved platelet counts, lactate dehydrogenase levels, and ADAMTS13 residual activity. In addition, GC1126A outperformed recombinant human wild-type ADAMTS13 (rh WT-ADAMTS13) and caplacizumab in terms of platelet recovery and sustained effectiveness. Results from the ex vivo study using plasma from patients with iTTP showed that GC1126A exhibited higher residual activity than rh WT-ADAMTS13, particularly in patients with high autoantibody titers. These findings suggest that GC1126A could be a promising new treatment option for patients with iTTP. |
| format | Article |
| id | doaj-art-09fa1ce272184dfcac2d29befcf99516 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-09fa1ce272184dfcac2d29befcf995162025-01-12T12:23:29ZengNature PortfolioScientific Reports2045-23222025-01-0115111310.1038/s41598-024-80674-xGC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpuraHeechun Kwak0Gahee Choi1Suyong Kim2Ji-Min Park3Youngeun Kwon4Yongmin Lee5Chaemok Lee6Shangbin Yang7Spero Cataland8Sunghyun Kim9Soo-Mee Bang10Jae-Ho Yoon11Wooin Lee12Hyun-Ja Nam13Discovery3 Team, Department of Research and Early Development, GC BiopharmaDiscovery3 Team, Department of Research and Early Development, GC BiopharmaDiscovery3 Team, Department of Research and Early Development, GC BiopharmaDiscovery3 Team, Department of Research and Early Development, GC BiopharmaDiscovery3 Team, Department of Research and Early Development, GC BiopharmaDiscovery3 Team, Department of Research and Early Development, GC BiopharmaDiscovery3 Team, Department of Research and Early Development, GC BiopharmaDivision of Hematology, Department of Medicine, The Ohio State UniversityDivision of Hematology, Department of Medicine, The Ohio State UniversityDepartment of Internal Medicine, Dong-A University Hospital, Dong-A University College of MedicineDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of MedicineDepartment of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National UniversityDiscovery3 Team, Department of Research and Early Development, GC BiopharmaAbstract Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening blood disorder characterized by the formation of blood clots in small blood vessels. It is caused by antibodies targeting the A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13), which plays a role in cleaving von Willebrand factor. Most patients with iTTP have autoantibodies against specific domains of the ADAMTS13 protein, particularly the cysteine-rich and spacer domains. This study aimed to identify ADAMTS13 muteins that are resistant to autoantibodies and maintain their enzymatic activity. A panel of muteins was generated using rational and random mutagenesis methods and screened for autoantibody binding and ADAMTS13 activity. The selected muteins were assessed for pharmacodynamic biomarkers and pharmacokinetic profiles in the iTTP-mimic and wild-type mice, respectively. GC1126A was the most effective variant for escaping autoantibodies and had a longer half-life than the wild-type ADAMTS13 fragment (MDTCS). In the iTTP-mimic mouse model, GC1126A treatment significantly improved platelet counts, lactate dehydrogenase levels, and ADAMTS13 residual activity. In addition, GC1126A outperformed recombinant human wild-type ADAMTS13 (rh WT-ADAMTS13) and caplacizumab in terms of platelet recovery and sustained effectiveness. Results from the ex vivo study using plasma from patients with iTTP showed that GC1126A exhibited higher residual activity than rh WT-ADAMTS13, particularly in patients with high autoantibody titers. These findings suggest that GC1126A could be a promising new treatment option for patients with iTTP.https://doi.org/10.1038/s41598-024-80674-x |
| spellingShingle | Heechun Kwak Gahee Choi Suyong Kim Ji-Min Park Youngeun Kwon Yongmin Lee Chaemok Lee Shangbin Yang Spero Cataland Sunghyun Kim Soo-Mee Bang Jae-Ho Yoon Wooin Lee Hyun-Ja Nam GC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpura Scientific Reports |
| title | GC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpura |
| title_full | GC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpura |
| title_fullStr | GC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpura |
| title_full_unstemmed | GC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpura |
| title_short | GC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpura |
| title_sort | gc1126a a novel adamts13 mutein evades autoantibodies in immune mediated thrombotic thrombocytopenic purpura |
| url | https://doi.org/10.1038/s41598-024-80674-x |
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