Immunotherapy for Factor VIII Inhibition in Hemophilia A

血友病A是最常见的X连锁隐性疾病之一，每5000名男婴中就有一名患病 全球范围内。静脉FVIII替代是护理治疗的标准，并在20-14岁的患者中对FVIII产生耐药性 30%的重症患者产生抗FVIII抗体(抑制剂)。临床免疫 消除抑制物的耐受诱导方案并不是对所有患者都有效，也没有批准的方案 抑制FVIII特异性抗体反应的预防方案。最近的研究结果表明， 对替换的FVIII蛋白的耐受性受到T调节细胞(Treg)的强烈调控。 Teichos实验室建议从其平台评估独一无二的免疫反应衰减剂TL-003 全合成肽聚糖(SPGN)分子诱导小鼠对凝血因子VIII的耐受性 血友病A.TL-003治疗在临床前模型中表现出低剂量的抗炎活性。这些 反应与体外发现TL-003不产生来自TLR2的刺激信号有关，不像 天然PGN和其他免疫反应激活剂sPGN。TL-003被单核细胞来源的人狂热摄取 树突状细胞。TL-003不上调抗原提呈细胞上的共刺激分子 外周血单核细胞(PBMCs)的治疗刺激抗炎的产生 细胞因子，IL-10。取消TLR2信号，减弱共刺激分子的上调，潜在 Treg的激活和体内的抗炎活性为评估免疫提供了令人信服的理由 反应衰减剂佐剂(TL-003)与重组治疗性蛋白抗原(FVIII)联合应用 耐受甲型血友病耐药疫苗治疗。 TL-003是通过化学酶过程合成的，该过程产生了原本无法获得的单链 细菌细胞壁肽聚糖。这种合成是高效的，可扩展的，可控制的，产生同质的， 可溶性、单链、未交联型PGN，分子量在抗体范围内。给出了分子 可使用工艺解决sPGN的特性、放大生产和化学制造问题 类似于标准药物开发中使用的那些。 这项提案的具体目标是建立支持临床的临床前参数 新型耐受疫苗佐剂TL-003治疗血友病A对第VIII因子耐药的研究 我们将1)准备sPGN测试文章和2)确定TL-003如何通过调制诱导外周(P)Treg 抗原提呈细胞(APC)和3)评估这种新的合成免疫反应衰减剂的效果 在已建立的血友病A小鼠模型中产生FVIII抑制剂。

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.