Induction of Tolerance to FVIII in Hemophilia

血友病中 FVIII 耐受的诱导

• 批准号: 9064200
• 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
• 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/9064200
• 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; 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; 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; 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（由申请人提供）：治疗具有因子 VIII (FVIII) 的 A 型血友病患者的一个主要问题是，这些患者中高达 30% 产生针对治疗性 FVIII 的抗体。这些抗体阻断（抑制）FVIII的促凝血功能，因此被称为“抑制剂”。我们实验室的重点是开发诱导耐受的新方法，以便将其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 B 淋巴细胞表达的免疫球蛋白 (Ig) 融合蛋白来诱导血友病动物模型的耐受性。该技术基于众所周知的 IgG 载体的耐受原性，我们在其 N 末端框内设计了多个含有表位的多肽。我们知道我们的耐受方案需要 CD4+CD25+ 调节性 T 细胞 (Treg)，并且已经表明 IgG 支架可提高该耐受过程的功效。独立数据表明 IgG 结构域含有称为 Tregitope 的表位，可以激活 Tregs。事实上，最近针对更长半衰期的 FVIII-Fc 融合蛋白的临床研究似乎免疫原性较低，并且可能具有耐受性。我们假设 Tregitopes 和 IgG 加工机制的存在促进了耐受性的呈现。我们在此提案中重点利用 IgG 融合蛋白（包括使用单链抗 CD20 的 B 细胞定向可溶性融合蛋白）的 B 细胞耐受性呈递，可用于诱导对 FVIII 的耐受并预防/逆转抑制剂形成。此外，来自血友病患者的 T 细胞受体 (TCR) 将用于创建抗原特异性效应细胞和调节性 CD4 T 细胞，类似于设计用于治疗 B 细胞白血病的 CAR19 T 细胞。这些将用于测试新型耐受性疗法以及工程化人类 Tregs 预防和逆转抑制剂形成的功效。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 反应性，最后 (2) 在扩增的人调节 T 细胞中表达 FVIII 特异性的人 TCR，以有效抑制对 FVIII 的抑制剂反应。阐明这些耐受性方法的机制将增强我们优化这种人类翻译方法的功效和安全性的能力。