ArticleProceedings of the National Academy of Sciences of the United States of America2007
A role for exposed mannosylations in presentation of human therapeutic self-proteins to CD4+ T lymphocytes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 121 citations in OpenAlex.
- Selective clearance of monoclonal antibodies via the mannose receptor is dependent on glycan pairing.Scientific reports · 2026Article
- Mechanisms of therapeutic antibodies immunogenicity: infliximab oligomeric aggregates increase T-cell response and uptake by dendritic cells involving mannose-sensitive receptor CD206.Frontiers in immunology · 2026Article
- A Deletion Variant of Human Factor VIII Displaying Low Immunogenicity in a Murine Model of Hemophilia A.International journal of molecular sciences · 2025Article
- Highly variable aggregation and glycosylation profiles and their roles in immunogenicity to protein-based therapeutics.Journal of pharmaceutical sciences · 2025Review
- Antigen-presenting cell internalization is key for understanding and evaluating therapeutic antibodies' immunogenicity.Frontiers in immunology · 2025Review
- Efanesoctocog alfa: the renaissance of Factor VIII replacement therapy.Haematologica · 2024Review
- Article
- A Mannose Receptor fromInternational journal of molecular sciences · 2023Article
- Influence of N-glycosylation in the A and C domains on the immunogenicity of factor VIII.Blood advances · 2022Article
- Removal of single-site N-linked glycans on factor VIII alters binding of domain-specific monoclonal antibodies.Journal of thrombosis and haemostasis : JTH · 2022Article
- Modulating the microenvironment during FVIII uptake influences the nature of FVIII-peptides presented by antigen-presenting cells.Frontiers in immunology · 2022Article
- Article
- Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2021Review
- The Mannose Receptor: From Endocytic Receptor and Biomarker to Regulator of (Meta)Inflammation.Frontiers in immunology · 2021Review
- Adeno-Associated Viruses (AAV) and Host Immunity - A Race Between the Hare and the Hedgehog.Frontiers in immunology · 2021Review
- AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Review
- Factor VIII Fc Fusion Protein but not FVIII Drives Human Monocyte-Derived Dendritic Cell Activation via FcγRIIa.HemaSphere · 2020Article
- Molecular Mechanisms of Inhibitor Development in Hemophilia.Mediterranean journal of hematology and infectious diseases · 2020Review
- Removal of Mannose-Ending Glycan at AsnFrontiers in immunology · 2020Article
- Immune Responses to Plasma-Derived Versus Recombinant FVIII Products.Frontiers in immunology · 2020Review
Corrections and comments
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Authors and funding
16 authors at 8 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Several therapeutic self-proteins elicit immune responses when administered to patients. Such adverse immune responses reduce drug efficacy. To induce an immune response, a protein must interact with different immune cells, including antigen-presenting cells, T cells, and B cells. Each cell type recognizes distinct immunogenic patterns on antigens. Mannose-terminating glycans have been identified as pathogen-associated molecular patterns that are essential for internalization of microbes by antigen-presenting cells, leading to presentation. Here, we have investigated the importance of exposed mannosylation on an immunogenic therapeutic self-protein, procoagulant human factor VIII (FVIII). Administration of therapeutic FVIII to hemophilia A patients induces inhibitory anti-FVIII antibodies in up to 30% of the cases. We demonstrate that entry of FVIII into human dendritic cells (DC) leading to T cell activation, is mediated by mannose-terminating glycans on FVIII. Further, we identified macrophage mannose receptor (CD206) as a candidate endocytic receptor for FVIII on DC. Saturation of mannose receptors on DC with mannan, and enzymatic removal of mannosylated glycans from FVIII lead to reduced T cell activation. The interaction between FVIII and CD206 was blocked by VWF, suggesting that, under physiological conditions, the intrinsic mannose-dependent immunogenicity of FVIII is quenched by endogenous immunochaperones. These data provide a link between the mannosylation of therapeutic self-proteins and their iatrogenic immunogenicity. Such a link would be of special relevance in the context of replacement therapy where mechanisms of central and peripheral tolerance have not been established during ontogeny because of the absence of the antigen.
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