Development of DRα1-MOG-35-55 for treatment of DR2 negative MS subjects

开发 DRα1-MOG-35-55 用于治疗 DR2 阴性多发性硬化症受试者

基本信息

  • 批准号:
    9046879
  • 负责人:
  • 金额:
    $ 22.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-02-01 至 2017-07-16
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Our laboratory discovered and is developing partial (p)MHC class II constructs (pMHC) as a possible immunotherapy for multiple sclerosis (MS). pMHC containing the extracellular domains of the MS risk factor, HLA-DR2, linked covalently to the encephalitogenic 35-55 peptide of myelin oligodendrocyte glycoprotein (pDR2/MOG-35-55) can reverse CNS inflammation and clinical signs of MOG-35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic mice. The pDR2/MOG-35-55 construct for humans (termed Recombinant T-cell receptor Ligand or RTL1000) was found to be safe and well tolerated in a Phase 1 safety trial in MS subjects and is soon to be tested in a Phase II tria in progressive MS. Our preclinical studies showed that pDR2/MOG-35-55 can specifically inhibit cognate DR2-restricted MOG-35-55 reactive T cells and to a lesser extent bystander T cells reactive to other myelin peptides. RTL1000 blocks the binding and downstream inflammatory effects of a key pathogenic factor in EAE and MS, called macrophage migration inhibitory factor (MIF), to CD74, the invariant chain (Ii) of MHC class II that serves as the major MIF receptor on immune cells. Additionally, the down-modulation of CD74 expression by RTL1000 may serve as an important biomarker of drug efficacy. Currently, the FDA requires that patients receiving RTL1000 express the same HLA-DR2 type as that intrinsic to RTL1000 in order to avoid potentially harmful transplantation "mismatches" after repeated dosing. "Matching" for HLA-DR2 would allow treatment of ~50% of MS subjects with RTL1000 (~250,000 Americans), but produces an unmet need for an effective pMHC treatment for the remaining 50% (~250,000) who express a variety of other HLA-DR types. To address this need, we here propose to evaluate the potency and immunogenicity of a novel derivative pMHC construct, DRα1-MOG-35-55, that retains the primary binding region for CD74 and the MOG-35-55 peptide found in RTL1000, but lacks the DR2β1 domain. Due to its universal expression, DRα1-MOG-35-55 would be a "match" for all human recipients and would thus nicely complement RTL1000 and address the unmet need of treating HLA-DR2 negative patients. To fully evaluate possible differences and limitations of each, we will compare potency, immunogenicity and CD74 modulation of the two constructs in "matched" (transgenic DR2+) vs. "mismatched" (transgenic DR4+) recipient mice with EAE. The ultimate goal of this study is to position the DRα1-MOG-35-55 drug to address the unmet need and provide coverage for DR2 negative MS subjects to complement the more advanced development of RTL1000 for use in DR2 positive MS subjects.
 描述(由申请人提供):我们的实验室发现并正在开发部分(p)MHC II类构建体(pMHC),作为多发性硬化症(MS)的可能免疫疗法。含有MS危险因子HLA-DR 2的细胞外结构域的pMHC与髓鞘少突胶质细胞糖蛋白的致脑炎35-55肽(pDR 2/MOG-35-55)共价连接,可以逆转DR 2转基因小鼠中的CNS炎症和MOG-35-55肽诱导的实验性自身免疫性脑脊髓炎(EAE)的临床体征。用于人的pDR 2/MOG-35-55构建体在MS受试者的I期安全性试验中发现pDR 2/MOG-35-55(称为重组T细胞受体配体或RTL 1000)是安全的且耐受性良好,并且很快将在进行性MS的II期试验中进行测试。55反应性T细胞和在较小程度上对其他髓鞘肽反应的旁观者T细胞。RTL 1000阻断EAE和MS中的关键致病因子(称为巨噬细胞迁移抑制因子(MIF))与CD 74的结合和下游炎症作用,CD 74是MHC II类的不变链(Ii),其充当免疫细胞上的主要MIF受体。此外,RTL 1000下调CD 74表达可作为药物疗效的重要生物标志物。目前,FDA要求接受RTL 1000的患者表达与RTL 1000内在相同的HLA-DR 2类型,以避免重复给药后潜在有害的移植“错配”。HLA-DR 2的“匹配”将允许用RTL 1000治疗约50%的MS受试者(约250,000名美国人),但对于表达各种其他HLA-DR类型的剩余50%(约250,000名)产生对有效pMHC治疗的未满足需求。为了满足这一需求,我们在此建议评估一种新型衍生pMHC构建体DRα1-MOG-35-55的效力和免疫原性,该构建体保留了RTL 1000中发现的CD 74和MOG-35-55肽的主要结合区域,但缺乏DR 2 β1结构域。由于其通用表达,DRα1-MOG-35-55将是所有人类受体的“匹配”,因此将很好地补充RTL 1000,并解决治疗HLA-DR 2阴性患者的未满足需求。为了充分评估每种可能的差异和局限性,我们将比较两种构建体在患有EAE的“匹配的”(转基因DR 2+)与“错配的”(转基因DR 4+)受体小鼠中的效力、免疫原性和CD 74调节。本研究的最终目标是定位DRα1-MOG-35-55药物,以解决未满足的需求,并为DR 2阴性MS受试者提供覆盖范围,以补充用于DR 2阳性MS受试者的RTL 1000的更先进开发。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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ARTHUR A. VANDENBARK其他文献

ARTHUR A. VANDENBARK的其他文献

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{{ truncateString('ARTHUR A. VANDENBARK', 18)}}的其他基金

Preclinical Translational Studies with DRHQ
DRHQ 的临床前转化研究
  • 批准号:
    10454781
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
Preclinical Translational Studies with DRHQ
DRHQ 的临床前转化研究
  • 批准号:
    10015855
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
Preclinical Translational Studies with DRHQ
DRHQ 的临床前转化研究
  • 批准号:
    10155078
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
Preclinical Translational Studies with DRHQ
DRHQ 的临床前转化研究
  • 批准号:
    10618863
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10265386
  • 财政年份:
    2018
  • 资助金额:
    $ 22.48万
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    9899089
  • 财政年份:
    2018
  • 资助金额:
    $ 22.48万
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10454215
  • 财政年份:
    2018
  • 资助金额:
    $ 22.48万
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10618286
  • 财政年份:
    2018
  • 资助金额:
    $ 22.48万
  • 项目类别:
Development of DRα1-MOG-35-55 for treatment of DR2 negative MS subjects
开发 DRα1-MOG-35-55 用于治疗 DR2 阴性多发性硬化症受试者
  • 批准号:
    9345703
  • 财政年份:
    2016
  • 资助金额:
    $ 22.48万
  • 项目类别:
Immunoregulation of Myelin Specific T Lymphocytes
髓磷脂特异性 T 淋巴细胞的免疫调节
  • 批准号:
    10343790
  • 财政年份:
    2009
  • 资助金额:
    $ 22.48万
  • 项目类别:

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