Induction of Tolerance to FVIII in Hemophilia

血友病中 FVIII 耐受的诱导

基本信息

批准号：
8858194
负责人：
David William Scott
金额：
$ 38.95万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-06 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8858194
关键词：
A Mouse Animal Model Antibodies Antibody Formation Antibody Response Antigens Autoimmune Diseases B-Lymphocytes Binding Blocking Antibodies Blood Coagulation Disorders Blood Coagulation Factor Blood coagulation C2 Domain CD4 Positive T Lymphocytes Catabolism Cell Proliferation Chimeric Proteins Chronic Lymphocytic Leukemia Clinic Clinical Research Coagulants Coagulation Process Data Disease Effector Cell Engineering Epitopes Factor VIII Frequencies Future Genes Goals Half-Life Health Hemophilia A Hemorrhage Human Human Engineering IL2RA gene Immune Immune response Immunoglobulin G Immunoglobulin Variable Region Immunoglobulins In Vitro Lead Lentivirus Vector Life Link MHC Class II Genes MS4A1 gene Maintenance Mediating Modeling Mus Mutate Mutation Pathway interactions Patients Peptides Plasma Play Prevention Process Proliferating Proteins Protocols documentation Recombinants Recycling Regulatory T-Lymphocyte Research Role Safety Structure T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Tolerogen Transgenes Transgenic Mice Translating Translations Treatment Efficacy base cellular transduction chimeric antigen receptor clinical efficacy cytokine design gene therapy immunogenic in vivo inhibitor/antagonist leukemia male neonatal Fc receptor novel novel strategies novel therapeutics polypeptide prevent response scaffold targeted delivery vector

项目摘要

DESCRIPTION (provided by applicant): A major problem in the treatment of hemophilia A patients with factor VIIII (FVIII) is that up to 30% of these patients produce antibodies to therapeutic FVIII. These antibodies block (inhibit) the pro- coagulant function of FVIII and thus are termed "inhibitors". The focus of our lab has been to develop novel approaches for the induction of tolerance so that it can be applied to the prevention or reversal of undesirable immune responses, including the formation of hemophilia inhibitors. We have used immunoglobulin (Ig) fusion proteins expressed in B lymphocytes for the induction of tolerance in animal models of hemophilia. This technology is based on the well-known tolerogenicity of IgG carriers, onto which we engineer multiple epitope-containing polypeptides in frame at the N-terminus. We know that CD4+CD25+ regulatory T cells (Tregs) are required in our tolerogenic protocol and have shown that that the IgG scaffold increases the efficacy of this tolerance process. Independent data suggests that IgG domains contain epitopes, termed Tregitopes, which can activate Tregs. Indeed, recent clinical studies with FVIII-Fc fusion proteins designed for longer half-life appear to be less immunogenic, and may be tolerogenic. We hypothesize that the presence of Tregitopes and IgG processing mechanisms promote tolerogenic presentation. We focus in this proposal to take advantage of B-cell tolerogenic presentation of IgG fusion proteins (including a B-cell directed soluble fusion protein using a single chain anti-CD20) that can be utilized to induce tolerance to FVIII and prevent/reverse inhibitor formation. Moreover, T-cell receptors (TCR) from hemophilia patients will be used to create antigen-specific effector and regulatory CD4 T cells in analogy to the CAR19 T cells designed to treat B-cell leukemias. These will be used to test novel tolerogenic therapy and the efficacy of engineered human Tregs to prevent and reverse inhibitor formation. Our ultimate Aims, thus, are: (1) to use B-cell targeted fusion proteins to modulate anti-FVIII responsiveness, and finally (2) to express human TCR specific for FVIII in expanded human regulatory T cells to effectively suppress inhibitor responses to FVIII. Elucidating the mechanisms of these tolerogenic approaches will enhance our ability to optimize the efficacy and safety of this approach for translation in humans.

描述（由适用提供）：治疗血友病A VIIII因子（FVIII）患者的一个主要问题是，这些患者中有多达30％的患者产生了治疗性FVIII的抗体。这些抗体阻滞（抑制）FVIII的促凝功能，因此称为“抑制剂”。我们实验室的重点是开发诱导耐受性的新方法，以便将其应用于预防或逆转不良免疫调查的，包括形成血友病抑制剂。我们已经使用了在B淋巴细胞中表达的免疫球蛋白（IG）融合蛋白来诱导血友病动物模型中的耐受性。这项技术基于IgG载体的众所周知的耐受性，我们在N末端的框架中设计了多个含多肽的多肽。我们知道，在我们的耐受性方案中需要CD4+ CD25+调节性T细胞（Treg），并表明IgG支架提高了这种耐受性过程的效率。独立的数据表明，IgG域包含表位，称为Tregitapes，可以激活Tregitapes。实际上，FVIII-FC融合蛋白的最新临床研究设计为更长的半衰期外观，其免疫原性较低，并且可能具有耐受性。我们假设tregitapes和IgG加工机制的存在促进了耐受性表现。我们重点关注该建议，以利用IgG融合蛋白（包括使用单个链抗CD20的B细胞融合蛋白的B细胞耐受性表示），可用于诱导FVIII的耐受性并预防/反向抑制剂形成。此外，血友病患者的T细胞受体（TCR）将用于与旨在治疗B细胞白血病的CAR19 T细胞相比，创建抗原特异性效应子和调节性CD4 T细胞。这些将用于测试新型的耐受性疗法以及工程人treg的有效性，以预防和逆转抑制剂形成。因此，我们的最终目的是：（1）使用B细胞靶向融合蛋白调节抗FVIII响应性，最后（2）表达对扩展的人类调节性T细胞中FVII的特异性人类TCR，以有效抑制抑制剂对FVIII的反应。阐明这些耐受性方法的机制将增强我们优化人类翻译方法的效率和安全性的能力。