ArticleThrombosis and haemostasis2017
Combination therapy for inhibitor reversal in haemophilia A using monoclonal anti-CD20 and rapamycin.
Article in Thrombosis and haemostasis, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 29 citations in OpenAlex.
- B cell-activating factor modulates the factor VIII immune response in hemophilia A.The Journal of clinical investigation · 2021Trial
- Enhancing AAV9-UFμDys1 Gene Therapy Efficacy Through Immunosuppression in Mice with Pre-Existing Immunity and Enabling Redosing Strategies for Duchenne Muscular Dystrophy.Human gene therapy · 2026Article
- Transplanted gene-modified placental cells boost FVIII activity in pediatric sheep without eliciting immunity, toxicity, or adverse events.Frontiers in immunology · 2025Article
- Prednisolone and rapamycin reduce the plasma cell gene signature and may improve AAV gene therapy in cynomolgus macaques.Gene therapy · 2024Article
- Article
- Suppression of anti-drug antibody formation against coagulation factor VIII by oral delivery of anti-CD3 monoclonal antibody in hemophilia A mice.Cellular immunology · 2023Article
- Oral tolerance to prevent anti-drug antibody formation in protein replacement therapies.Cellular immunology · 2022Review
- Single-dose AAV vector gene immunotherapy to treat food allergy.Molecular therapy. Methods & clinical development · 2022Article
- Article
- CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Effect of Subcutaneous Anti-CD20 Antibody-Mediated B Cell Depletion on Susceptibility to Pneumocystis Infection in Mice.mSphere · 2021Article
- Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.Journal of controlled release : official journal of the Controlled Release Society · 2021Article
- Combined anti-CD20 and mTOR inhibition with factor VIII for immune tolerance induction in hemophilia A patients with refractory inhibitors.Journal of thrombosis and haemostasis : JTH · 2020Article
- Factor VIII: Perspectives on Immunogenicity and Tolerogenic Strategies for Hemophilia A Patients.International journal of molecular and cellular medicine · 2020Review
- B Cell Depletion Eliminates FVIII Memory B Cells and Enhances AAV8-coF8 Immune Tolerance Induction When Combined With Rapamycin.Frontiers in immunology · 2020Article
- Fc Gamma Receptors and Complement Component 3 Facilitate Anti-fVIII Antibody Formation.Frontiers in immunology · 2020Article
- Escape or Fight: Inhibitors in Hemophilia A.Frontiers in immunology · 2020Review
- Complexity of immune responses to AAV transgene products - Example of factor IX.Cellular immunology · 2019Review
- Update on clinical gene therapy for hemophilia.Blood · 2019Review
- Reprogrammed CD4Frontiers in immunology · 2019Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Development of antibodies (inhibitors) against coagulation factor VIII (FVIII) is a major complication of intravenous replacement therapy in haemophilia A (HA). Current immune tolerance induction (ITI) regimens are not universally effective. Rituximab, a B cell-depleting antibody against CD20, has shown mixed results for inhibitor reversal in patients. This study aims to develop a combinatorial therapy for inhibitor reversal in HA, using anti-murine CD20 (anti-mCD20) antibody and rapamycin, which targets both B and T cell responses. Additionally, it extensively characterises the role of the IgG backbone in B cell depletion by anti-CD20 antibodies. For this, inhibitors were generated in BALB/c-HA mice by weekly IV injection of FVIII. Subsequently, anti-mCD20 (18B12) with IgG2a or IgG1 backbone was injected IV in two doses three weeks apart and B cell depletion and recovery was characterised. Rapamycin was administered orally 3x/week (for 1 month) while continuing FVIII injections. Altering the IgG backbone of anti-mCD20 from IgG2a to IgG1 reduced overall depletion of B cells (including memory B cells), and marginal zone, B-10, and B-1b cells were specifically unaffected. While neither antibody was effective alone, in combination with rapamycin, anti-mCD20 IgG2a but not IgG1 was able to reverse inhibitors in HA mice. This regimen was particularly effective for starting titres of ~10 BU. Although IgG1 anti-mCD20 spared potentially tolerogenic B cell subsets, IgG2a directed sustained hyporesponsiveness when administered in conjunction with rapamycin. This regimen represents a promising treatment for inhibitor reversal in HA, as both of these compounds have been extensively used in human patients.
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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.