Immunotherapy for Factor VIII Inhibition in Hemophilia A

血友病 A 中因子 VIII 抑制的免疫疗法

• 批准号: 10484774
• 负责人: Larry C. Blaszczak
• 金额: $ 25.96万
• 依托单位: TEICHOS LABORATORIES, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484774
• 关键词: Adjuvant; Affect; Animals; Anti-Inflammatory Agents; Antibodies; Antibody Response; Antibody Therapy; Antigen-Presenting Cells; Antigens; Attenuated; Autoimmunity; Award; B-Lymphocytes; Birth; Cell Culture Techniques; Cell Wall; Cells; Chemicals; Chemistry; Clinical; Dendritic Cells; Development; Disease; Dose; Endotoxins; Excision; F8 gene; Factor VIII; Flow Cytometry; Frequencies; Genetic; Grant; Hemophilia A; Immune; Immune Tolerance; Immune response; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Interferons; Interleukin-10; Interleukin-2; Intravenous; Laboratories; Laboratory Study; Link; Lipids; Measures; Mediating; Messenger RNA; Modeling; Modification; Molecular; Molecular Weight; Mus; Natural Killer Cells; Patients; Peptidoglycan; Peripheral; Peripheral Blood Mononuclear Cell; Pharmacologic Substance; Phase; Phenotype; Physical condensation; Plasma; Population; Pre-Clinical Model; Process; Production; Property; Proteins; Protocols documentation; Publications; Receptor Signaling; Recombinants; Regulatory T-Lymphocyte; Replacement Therapy; Reporting; Research; Resistance; Resistance development; Resource Allocation; Signal Transduction; Sirolimus; Small Business Innovation Research Grant; Spleen; Sterility; Structure; T-Lymphocyte Subsets; TLR2 gene; TLR7 gene; TNF gene; Testing; Toll-like receptors; Toxic effect; Up-Regulation; Vaccine Adjuvant; Vaccine Therapy; Vaccines; Validation; adaptive immunity; antibody inhibitor; chemical synthesis; clinical development; cytokine; effectiveness evaluation; effector T cell; enzyme replacement therapy; exhaustion; experimental study; improved; in vivo; inhibitor; lymph nodes; mTOR Inhibitor; male; monocyte; mouse model; neutrophil; novel; polymerization; pre-clinical; prophylactic; response; scale up; standard of care; therapeutic protein; therapy outcome; treatment response

Hemophilia A is one of the most common X-linked recessive disorders, affecting one in 5,000 male births globally. Intravenous FVIII replacement is the standard of care therapy and resistance develops to FVIII in 20– 30% of patients with severe disease from the production of anti-FVIII antibodies (inhibitors). Clinical immune tolerance induction protocols to eliminate inhibitors are not effective in all patients, and there are no approved prophylactic protocols to suppress FVIII-specific antibody responses. Recent findings have reported that tolerance to replacement FVIII protein is strongly modulated by T regulatory cells (Treg). Teichos Laboratories proposes to evaluate TL-003, a unique immune response attenuator from its platform of totally synthetic peptidoglycan (sPGN) molecules for tolerance induction against Factor VIII resistance in Hemophilia A. TL-003 treatment produced anti-inflammatory activity at low doses in preclinical models. These responses were associated with in vitro findings that TL-003 produces no stimulatory signal from TLR2, unlike natural PGN and other immune response activator sPGNs. TL-003 is taken up avidly by monocyte-derived dendritic cells (DC). TL-003 does not up-regulate costimulatory molecules on antigen presenting cells (APCs) and treatment of peripheral blood mononuclear cells (PBMCs) stimulates production of the anti-inflammatory cytokine, IL-10. Abrogation of TLR2 signalling, diminished up-regulation of costimulatory molecules, potential activation of Treg, and in vivo anti-inflammatory activity provide a compelling rationale to evaluate an immune response attenuator adjuvant (TL-003) combined with a recombinant therapeutic protein antigen (FVIII) in a tolerizing vaccine therapy for Hemophilia A resistance. TL-003 is synthesized by a chemoenzymatic process that produces otherwise inaccessible single-strand bacterial cell wall peptidoglycan. This synthesis is efficient, scalable, and controllable, producing homogenous, soluble, single strand, uncrosslinked PGN with molecular weight in the antibody range. Given the molecular properties of sPGN, scale-up production and chemical manufacturing issues are addressable using processes similar to those employed in standard pharmaceutical development. The Specific Aims of this proposal are to establish preclinical parameters that will support clinical development of TL-003 as a new tolerizing vaccine adjuvant to treat Factor VIII resistance in Hemophilia A. We will 1) prepare sPGN test articles and 2) determine how TL-003 induces peripheral (p) Treg via modulation of antigen presenting cells (APC) and 3) evaluate the effects of this new synthetic immune response attenuator on the production of FVIII inhibitors in an established mouse model of Hemophilia A.

血友病A是最常见的X连锁隐性遗传疾病之一，每5,000名男婴中就有一名患有血友病A。 在全球静脉内FVIII替代是标准治疗，在20- 30岁的儿童中， 30%的重度疾病患者产生抗FVIII抗体（抑制剂）。临床免疫 消除抑制剂的耐受性诱导方案并不是对所有患者都有效， 预防性方案以抑制FVIII特异性抗体应答。最近的调查结果表明， 对替换FVIII蛋白的耐受性受到T调节细胞（Treg）的强烈调节。 Teichos实验室建议评估TL-003，一种独特的免疫反应衰减剂， 全合成肽聚糖（sPGN）分子对凝血因子VIII耐药性的耐受性诱导， A型血友病TL-003治疗在临床前模型中以低剂量产生抗炎活性。这些 反应与体外发现有关，TL-003不产生来自TLR 2的刺激信号， 天然PGN和其它免疫应答激活剂sPGN。TL-003被单核细胞衍生的 树突状细胞（DC）。TL-003不上调抗原呈递细胞（APC）上的共刺激分子 外周血单核细胞（PBMC）的治疗刺激抗炎因子的产生， 细胞因子IL-10。TLR 2信号传导的消除，共刺激分子的上调减少， Treg的激活和体内抗炎活性提供了一个令人信服的理由来评估免疫调节剂的作用。 反应衰减剂佐剂（TL-003）与重组治疗性蛋白抗原（FVIII）组合， 对血友病A耐药的耐受性疫苗治疗。 TL-003是通过化学酶促过程合成的，该过程产生否则难以获得的单链 细菌细胞壁肽聚糖。该合成是有效的、可扩展的和可控的，产生均质的， 分子量在抗体范围内的可溶性单链未交联PGN。考虑到分子 sPGN的性质、规模化生产和化学品制造问题可使用以下方法解决： 类似于标准药物开发中使用的那些。 本提案的具体目的是建立临床前参数，以支持临床 TL-003作为一种新的耐受性疫苗佐剂，用于治疗血友病A中的因子VIII耐药性。 我们将1）制备sPGN测试制品和2）确定TL-003如何通过调节诱导外周（p）Treg 的抗原呈递细胞（APC）和3）评估这种新的合成免疫应答衰减剂的作用 在已建立的血友病A小鼠模型中对FVIII抑制剂产生的影响。