ArticleThe Journal of biological chemistry2005
Lower inhibitor development in hemophilia A mice following administration of recombinant factor VIII-O-phospho-L-serine complex.
Article in The Journal of biological chemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 46 citations in OpenAlex.
- Immune tolerance platforms to mitigate unwanted immune responses.Journal of pharmaceutical sciences · 2026Review
- Immune regulatory adjuvant approach to mitigate subcutaneous immunogenicity of monoclonal antibodies.Frontiers in immunology · 2024Article
- Stable binding to phosphatidylserine-containing membranes requires conserved arginine residues in tandem C domains of blood coagulation factor VIII.Frontiers in molecular biosciences · 2022Article
- Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2021Review
- Biological Function and Immunotherapy Utilizing Phosphatidylserine-based Nanoparticles.Immunological investigations · 2020Review
- Phosphatidylserine Is Not Just a Cleanup Crew but Also a Well-Meaning Teacher.Journal of pharmaceutical sciences · 2018Article
- Phosphatidylserine Converts Immunogenic Recombinant Human Acid Alpha-Glucosidase to a Tolerogenic Form in a Mouse Model of Pompe Disease.Journal of pharmaceutical sciences · 2016Article
- Effect of Biophysical Properties of Phosphatidylserine Particle on Immune Tolerance Induction Toward Factor VIII in a Hemophilia A Mouse Model.Journal of pharmaceutical sciences · 2016Article
- Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration.Biopharmaceutics & drug disposition · 2015Article
- Intravenous administration of Factor VIII-O-Phospho-L-Serine (OPLS) complex reduces immunogenicity and preserves pharmacokinetics of the therapeutic protein.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2015Article
- Agile delivery of protein therapeutics to CNS.Journal of controlled release : official journal of the Controlled Release Society · 2014Review
- Effects of replacement of factor VIII amino acids Asp519 and Glu665 with Val on plasma survival and efficacy in vivo.The AAPS journal · 2014Article
- Immunogenicity of subcutaneously administered therapeutic proteins--a mechanistic perspective.The AAPS journal · 2013Review
- Exposure to factor VIII protein in the presence of phosphatidylserine induces hypo-responsiveness toward factor VIII challenge in hemophilia A mice.The Journal of biological chemistry · 2013Article
- Native-like aggregates of factor VIII are immunogenic in von Willebrand factor deficient and hemophilia a mice.Journal of pharmaceutical sciences · 2012Article
- PEGylation of a factor VIII-phosphatidylinositol complex: pharmacokinetics and immunogenicity in hemophilia A mice.The AAPS journal · 2012Article
- Phospholipid binding lowers immunogenicity of human recombinant factor VIII in von Willebrand factor knockout mice.Thrombosis and haemostasis · 2011Article
- Immunogenicity and pharmacokinetic studies of recombinant factor VIII containing lipid cochleates.Drug delivery · 2011Article
- Phosphatidylserine reduces immune response against human recombinant Factor VIII in Hemophilia A mice by regulation of dendritic cell function.Clinical immunology (Orlando, Fla.) · 2011Article
- In vitro immunogenicity risk assessment of therapeutic proteins in preclinical setting.Methods in molecular biology (Clifton, N.J.) · 2011Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Factor VIII is a multidomain protein composed of A1, A2, B, A3, C1, and C2 domains. Deficiency or dysfunction of factor VIII causes hemophilia A, a bleeding disorder. Administration of exogenous recombinant factor VIII as a replacement leads to development of inhibitory antibodies against factor VIII in 15-30% of hemophilia A patients. Hence, less immunogenic preparations of factor VIII are highly desirable. Inhibitory antibodies against factor VIII are mainly directed against immunodominant epitopes in C2, A3, and A2 domains. Further, several universal epitopes for CD4+ T-cells have been identified within the C2 domain. The C2 domain is also known to interact specifically with phosphatidylserine-rich lipid vesicles. Here, we have investigated the hypothesis that complexation of O-phospho-l-serine, the head group of phosphatidylserine, with the C2 domain can reduce the overall immunogenicity of factor VIII. The biophysical (circular dichroism and fluorescence) and biochemical studies (ELISA and size exclusion chromatography) showed that O-phospho-l-serine binds to the phospholipid-binding region in the C2 domain, and this interaction causes subtle changes in the tertiary structure of the protein. O-Phospho-l-serine also prevented aggregation of the protein under thermal stress. The immunogenicity of the factor VIII-O-phospho-l-serine complex was evaluated in hemophilia A mice. The total and inhibitory antibody titers were lower for factor VIII-O-phospho-l-serine complex compared with factor VIII alone. Moreover, factor VIII administered as a complex with O-phospho-l-serine retained in vivo activity in hemophilia A mice. Our results suggest that factor VIII-O-phospho-l-serine complex may be beneficial to increase the physical stability and reduce immunogenicity of recombinant factor VIII preparations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.