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（由申请人提供）：大约30％的先天性血友病A（HA）患者会产生同种抗体，以中和替代因子的活性（F）VIII蛋白。在非裔美国人HA患者中，抑制剂形成的频率要高得多。约50％。抑制剂患者通常用旁观药物治疗。与FVIII完全控制出血相比，绕过代理更昂贵，效果更低。慢性出血成关节 与可以通过替换FVIII进行管理的HA患者相比，引起抑制剂患者需要进行更多骨科手术并经历降低的活动能力。尽管引入了大约40种FVIII产品，但自1970年代以来，抑制剂的形成速率一直保持恒定。接受长期，艰巨且非常昂贵的疗法，称为免疫耐受性诱导（ITI），是消除HA患者抑制剂的唯一手段。 ITI所需的FVIII量和治疗的强度导致每位抑制剂患者的成本在500,000-1,000,000美元之间。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可能降低了非裔美国人HA抑制剂患者的功效。我们的调查人员团队正在开发一种个性化的药物基因组方法来治疗HA。该方法可以应用于遏制抑制剂形成的发作并消除现有的抑制剂。这种方法的基石涉及确定HA患者内源性FVIII蛋白和候选FVIII产品之间的结构差异。大多数HA患者具有基本完整的FVIII分子，并有望容忍其内源性FVIII。因此，对于大多数HA患者而言，FVIII替代的元素具有触发免疫反应的潜力，称为T细胞表位，驻留在一个或多个非常离散的FVIII部分中，并且容易受到识别。最近据报道，可以通过开采打捞途径来实现抗原特异性耐受性。具体而言，在多发性硬化症的小鼠模型中，涂有髓磷脂的肽涂有肽的微粒静脉输送。在该项目中，我们将评估类似的方法是否具有防止或减轻对FVIII治疗的免疫反应的实用性。我们将通过管理旨在免疫原性的FVIII构建体来进行的，该构建体对人类FVIII具有耐受性的耐受性为生。 FVIII免疫原子将是功能性的FVIII分子，其中猪FVIII的肽序列已被替代在FVIII部位的人类序列，已知是对FVIII免疫反应的靶标。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为止。 我们将检验以下假设：在我们的FVIII免疫原中设计的与T细胞表位相同的肽涂有肽的静脉输送，将在这种临床上相关的HA模型中先发出或静音对免疫原性FVIII蛋白的免疫反应。