Novel pharmacogenomic approach for identifying T cell epitopes in replacement FVI

用于识别替代 FVI 中 T 细胞表位的新药物基因组学方法

• 批准号: 8646315
• 负责人: James W Lillard
• 金额: $ 20.38万
• 依托单位: HAPLOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-23 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646315
• 关键词: Abate; African; African American; Aftercare; Amino Acids; Antibodies; Antibody Formation; Antigens; Autoimmune Process; Biological Assay; Bypass; Carbodiimides; Childhood; Chronic; Clinical; Clip; Coagulation Process; Collaborations; Coupled; Development; Disease; Doctor of Philosophy; Dose; Engineering; Epitopes; Ethylenes; European; Experimental Autoimmune Encephalomyelitis; F Factor; FDA approved; Family suidae; Frequencies; Genetic; Germany; Glycolic-Lactic Acid Polyester; Haplotypes; Hemophilia A; Hemorrhage; Heterogeneity; Human; Immune Tolerance; Immune response; Indium; Individual; Infusion procedures; Intravenous; Isoantibodies; Joints; Laboratories; Letters; Methionine; Methods; Modeling; Morbidity - disease rate; Morehouse School of Medicine; Multiple Sclerosis; Mus; Myelin; Orthopedic Surgery procedures; Pain; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacogenomics; Physicians; Plasma; Positioning Attribute; Preparation; Procedures; Proteins; Protocols documentation; Recombinants; Replacement Therapy; Reporting; Research Personnel; Risk; Site; Source; Structure; Symptoms; T cell response; T-Lymphocyte Epitopes; Tail; Techniques; Testing; Time; Valine; base; clinically relevant; cost; design; design and construction; effective therapy; experience; immunogenic; immunogenicity; in vivo; inhibitor/antagonist; mouse model; novel; novel strategies; preempt; prevent; protein aminoacid sequence; public health relevance; reconstitution; response

DESCRIPTION (provided by applicant): About 30% of congenital Hemophilia A (HA) patients develop alloantibodies that neutralize the activity of replacement Factor (F) VIII proteins. Among African American HA patients, the frequency of inhibitor formation is much higher; about 50%. Inhibitor patients are typically treated with bypassing agents. Bypassing agents are more expensive and less effective than FVIII in fully controlling bleeding. Chronic bleeding into joints causes inhibitor patients to require more orthopedic surgeries and to experience reduced mobility, in comparison to HA patients who can be managed with replacement FVIII. Despite the introduction of some 40 FVIII products, the rate of inhibitor formation has remained constant since the 1970s. Undergoing a lengthy, arduous and very expensive therapy, known as immune tolerance induction (ITI), is the only means available to eradicate inhibitors in HA patients. The amount of FVIII required for ITI and the intensity of the treatment result in costs ranging from $500,000-$1,000,000 per inhibitor patient. Unfortunately, ITI fails in about 30% of patients. At least one clinical report suggests ITI may have reduced efficacy in African American HA inhibitor patients. Our team of investigators is developing a personalized, pharmacogenomic approach for treating HA. This approach may be applied to curb the onset of inhibitor formation and to eradicate extant inhibitors. A cornerstone of this approach involves determining structural differences between the HA patient's endogenous FVIII protein and candidate replacement FVIII products. The majority of HA patients make a substantially complete FVIII molecule and are expected to be tolerized to their endogenous FVIII. It follows that for most HA patients, elements in replacement FVIII having the potential to trigger an immune response, termed T cell epitopes, reside in one or more very discrete sections of the replacement FVIII, and are susceptible to identification. It has recently been reported that antigen specific tolerance may be achieved through exploitation of a salvage pathway. Specifically, intravenous delivery of microparticles coated with peptides derived from myelin, abated an autoimmune attack of "self-myelin" in a mouse model of multiple sclerosis. In this project, we will evaluate whether a similar approach has utility for preventing or abating the immune response to FVIII therapy. We will do so by administering FVIII constructs designed to be immunogenic to a hemophilic mouse that has been engineered to be tolerant to human FVIII. The FVIII immunogens will be fully functional FVIII molecules in which peptide sequences from porcine FVIII have been substituted for human sequence at sites of FVIII known to be the target of the immune response to FVIII. As in HA patients, the FVIII proteins will control bleeding in the model until high titer inhibitors emerge. We will test the hypothesis that intravenous delivery of microparticles coated with peptides identical in structure to the T cell epitopes engineered into our FVIII immunogens, will preempt or mute the immune response to the immunogenic FVIII proteins in this clinically relevant model of HA.

描述（由申请方提供）：约30%的先天性血友病A（HA）患者产生了中和因子（F）VIII替代蛋白活性的同种抗体。在非洲裔美国人HA患者中，抑制物形成的频率要高得多;约50%。抑制剂患者通常用旁路药物治疗。止血剂比FVIII更昂贵，在完全控制出血方面效果更差。关节慢性出血 导致抑制剂患者需要更多的骨科手术，并经历减少的流动性相比，HA患者谁可以与替代FVIII管理。尽管引入了约40种FVIII产品，但自20世纪70年代以来，抑制剂形成的速率一直保持不变。进行一个漫长的，艰苦的和非常昂贵的治疗，称为免疫耐受诱导（ITI），是唯一的手段，可消除抑制剂在HA患者。ITI所需的FVIII量和治疗强度导致每个抑制剂患者的成本范围为500，000 - 1，000，000美元。不幸的是，ITI在大约30%的患者中失败。至少有一份临床报告表明，ITI可能降低了非洲裔美国人HA抑制剂患者的疗效。我们的研究团队正在开发一种个性化的药物基因组学方法来治疗HA。这种方法可用于抑制抑制剂形成的发生并根除现存的抑制剂。该方法的基础包括确定HA患者的内源性FVIII蛋白和候选替代FVIII产物之间的结构差异。大多数HA患者产生基本上完整的FVIII分子，并且预期对其内源性FVIII耐受。因此，对于大多数HA患者，替代FVIII中具有触发免疫应答潜力的元件（称为T细胞表位）存在于替代FVIII的一个或多个非常离散的部分中，并且易于识别。最近有报道，抗原特异性耐受性可以通过利用补救途径来实现。具体而言，静脉内递送涂覆有源自髓鞘的肽的微粒减轻了多发性硬化症小鼠模型中“自身髓鞘”的自身免疫攻击。在本项目中，我们将评估类似的方法是否可用于预防或减轻对FVIII治疗的免疫应答。我们将通过向血友病小鼠施用设计为具有免疫原性的FVIII构建体来实现这一点，所述血友病小鼠已被工程改造为对人FVIII具有耐受性。FVIII免疫原将是全功能的FVIII分子，其中来自猪FVIII的肽序列已经在已知是对FVIII的免疫应答的靶标的FVIII位点处取代了人序列。与HA患者一样，FVIII蛋白将控制模型中的出血，直到出现高滴度抑制剂。 我们将检验这样的假设，即静脉内递送包被有在结构上与工程化到我们的FVIII免疫原中的T细胞表位相同的肽的微粒将在这种临床相关的HA模型中抢先或沉默对免疫原性FVIII蛋白的免疫应答。