Induction of Tolerance to FVIII in Hemophilia

血友病中 FVIII 耐受的诱导

• 批准号: 9260046
• 负责人: David William Scott
• 金额: $ 47.33万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 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/9260046
• 关键词: Animal Model; Antibodies; Antibody Formation; Antibody Response; Antigens; Autoimmune Diseases; B-Cell Leukemia; B-Lymphocytes; Binding; Blocking Antibodies; Blood Coagulation Disorders; Blood Coagulation Factor; Blood coagulation; C2 Domain; CD4 Positive T Lymphocytes; Catabolism; Cell Proliferation; Chimeric Proteins; Clinic; Clinical Research; Clone Cells; Coagulation Process; Data; Disease; Effector Cell; Engineering; Epitopes; F8 gene; Factor VIII; Frequencies; Future; Genes; Goals; Half-Life; Hemophilia A; Hemorrhage; Human; Human Engineering; IL2RA gene; Immune; Immune response; Immunize; Immunoglobulin G; Immunoglobulin Variable Region; Immunoglobulins; In Vitro; Intravenous; 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; Protein Engineering; 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; public health relevance; response; scaffold; targeted delivery; vector

 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(申请人提供)：使用凝血因子VIIII(FVIII)治疗血友病A患者的一个主要问题是，高达30%的患者产生治疗性FVIII抗体。这些抗体阻断(抑制)FVIII的促凝血功能，因此被称为“抑制物”。我们实验室的重点一直是开发诱导耐受的新方法，以便它可以应用于预防或逆转不良免疫反应，包括血友病抑制剂的形成。我们使用在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的耐受。这项技术是基于众所周知的免疫球蛋白载体的耐受性，在其上我们在N端的框架内设计了多个含有表位的多肽。我们知道，在我们的耐受性方案中，CD4+CD25+调节性T细胞(Tregs)是必需的，并且已经表明，免疫球蛋白支架提高了这一耐受过程的有效性。独立数据表明，Ig G结构域含有表位，称为Tregitope，可以激活Tregs。事实上，最近关于FVIII-Fc融合蛋白的临床研究设计的半衰期更长，似乎免疫原性较低，可能具有耐受性。我们假设，三倍体的存在和免疫球蛋白的处理机制促进了耐受性的呈现。在这个提议中，我们的重点是利用B细胞耐受的融合蛋白(包括使用单链抗CD20的B细胞定向的可溶性融合蛋白)，可以用来诱导对FVIII的耐受和防止/逆转抑制物的形成。此外，血友病患者的T细胞受体(TCR)将被用来产生抗原特异性效应器和调节性CD4T细胞，类似于设计用于治疗B细胞白血病的cAR19T细胞。这些将被用来测试新的耐受疗法和工程人Tregs预防和逆转抑制剂形成的有效性。因此，我们的最终目标是：(1)使用B细胞靶向融合蛋白来调节抗FVIII的反应，最后(2)在扩增的人调节性T细胞中表达针对FVIII的人TCR，以有效地抑制对FVIII的抑制反应。阐明这些耐受性方法的机制将增强我们优化这种方法在人类身上的有效性和安全性的能力。