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

基本信息

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
项目类别：
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

项目摘要

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）：约 30% 的先天性 A 型血友病 (HA) 患者会产生可中和替代因子 (F) VIII 蛋白活性的同种抗体。在非裔美国 HA 患者中，抑制物形成的频率要高得多；约50%。抑制剂患者通常使用旁路药物进行治疗。旁路药物在完全控制出血方面比 FVIII 更昂贵且效果较差。关节慢性出血与可以通过替代 FVIII 治疗的 HA 患者相比，FVIII 抑制剂患者需要更多的骨科手术，并且活动能力下降。尽管推出了约 40 种 FVIII 产品，但自 20 世纪 70 年代以来抑制剂的形成率一直保持稳定。接受漫长、艰苦且非常昂贵的治疗，称为免疫耐受诱导（ITI），是根除 HA 患者体内抑制剂的唯一方法。 ITI 所需的 FVIII 量和治疗强度导致每位抑制剂患者的费用从 500,000 美元到 1,000,000 美元不等。不幸的是，约 30% 的患者 ITI 失败。至少一份临床报告表明 ITI 可能会降低非裔美国 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。该方法可用于抑制抑制剂形成的发生并消除现有的抑制剂。该方法的基石包括确定 HA 患者的内源性 FVIII 蛋白和候选替代 FVIII 产品之间的结构差异。大多数 HA 患者产生基本上完整的 FVIII 分子，并且预计对其内源性 FVIII 具有耐受性。由此可见，对于大多数 HA 患者来说，替代 FVIII 中具有触发免疫反应潜力的元素（称为 T 细胞表位）驻留在替代 FVIII 的一个或多个非常离散的部分中，并且易于识别。最近有报道称，抗原特异性耐受可以通过利用补救途径来实现。具体来说，静脉内输送涂有髓磷脂衍生肽的微粒，可以减轻多发性硬化症小鼠模型中“自身髓磷脂”的自身免疫攻击。在这个项目中，我们将评估类似的方法是否可用于预防或减轻 FVIII 治疗的免疫反应。我们将通过给血友病小鼠施用设计为具有免疫原性的 FVIII 构建体来实现这一目标，该血友病小鼠已被改造为对人 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的肽序列已在已知为针对FVIII的免疫应答的靶标的FVIII位点处替换为人序列。与 HA 患者一样，FVIII 蛋白将控制模型中的出血，直到出现高效价抑制剂。我们将测试这样的假设：静脉注射涂有肽的微粒，其结构与设计到我们的 FVIII 免疫原中的 T 细胞表位相同，将在这个临床相关的 HA 模型中抢占或减弱对免疫原性 FVIII 蛋白的免疫反应。