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：
ARTHUR A. VANDENBARK
金额：
$ 22.48万
依托单位：
VIROGENOMICS BIODEVELOPMENT, INC.
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

来源：
https://reporter.nih.gov/project-details/9046879
关键词：
Acute Address Advanced Development American Animal Model Arthritis Autoimmune Diseases Berylliosis Binding Biological Biological Markers Blood Celiac Disease Cells Chronic Clinical Clinical Trials Complement Complex Development Disease Disease susceptibility Dose Experimental Autoimmune Encephalomyelitis Extracellular Domain Female Goals HLA-DR Antigens HLA-DR2 Antigen HLA-DR4 Antigen Human Immune Immunotherapy Inflammation Inflammatory Laboratories Letters Ligands Link MHC Class II Genes Migration Inhibitory Factor Multiple Sclerosis Mus Myelin Orphan Drugs Patients Peptide/MHC Complex Peptides Pharmaceutical Preparations Phase Phase I Clinical Trials Positioning Attribute Preparation Reading Recombinants Risk Factors Safety Stroke T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte TNFRSF10A gene Testing Therapeutic Transgenic Mice Transgenic Organisms Transplantation Treatment Efficacy Work cytokine design drug efficacy genetic risk factor immunogenic immunogenicity invariant chain male methamphetamine abuse monocyte neutralizing antibody novel novel therapeutics oligodendrocyte-myelin glycoprotein phenylpyruvate tautomerase preclinical study public health relevance receptor

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，其中包含 MS 危险因子 HLA-DR2 的细胞外结构域。与髓鞘少突胶质细胞糖蛋白 (pDR2/MOG-35-55) 的致脑炎 35-55 肽共价连接可以逆转中枢神经系统炎症DR2 转基因小鼠中 MOG-35-55 肽诱导的实验性自身免疫性脑脊髓炎 (EAE) 的临床症状被发现用于人类的 pDR2/MOG-35-55 构建体（称为重组 T 细胞受体配体或 RTL1000）是安全的。在 MS 受试者的 1 期安全性试验中具有良好的耐受性，并且很快将在进行性 MS 的 II 期试验中进行测试。研究表明，pDR2/MOG-35-55 可以特异性抑制同源 DR2 限制性 MOG-35-55 反应性 T 细胞，并在较小程度上抑制与其他髓磷脂肽反应的旁观者 T 细胞，阻断关键致病性的结合和下游炎症效应。 EAE 和 MS 中的因子，称为巨噬细胞迁移抑制因子 (MIF)，与 CD74（MHC II 类的不变链 (Ii)）作用此外，RTL1000 对 CD74 表达的下调可能作为药物疗效的重要生物标志物，目前 FDA 要求接受 RTL1000 的患者表达与固有的 HLA-DR2 类型相同的 HLA-DR2 类型。 RTL1000 是为了避免重复给药后潜在有害的移植“错配”，HLA-DR2 的“匹配”将允许约 50% 的 MS 受试者接受治疗。 RTL1000（约 250,000 名美国人），但对表达各种其他 HLA-DR 类型的其余 50%（约 250,000 名）产生了有效 pMHC 治疗的需求未得到满足。新型衍生 pMHC 构建体 DRα1-MOG-35-55 的免疫原性，保留了 CD74 的主要结合区和MOG-35-55 肽存在于 RTL1000 中，但缺乏 DR2β1 结构域，由于其通用表达，DRα1-MOG-35-55 将“匹配”所有人类受体，从而很好地补充 RTL1000 并解决未满足的需求。为了充分评估每种结构可能的差异和局限性，我们将比较两种构建体的效力、免疫原性和 CD74 调节。患有 EAE 的“匹配”（转基因 DR2+）与“不匹配”（转基因 DR4+）受体小鼠本研究的最终目标是定位 DRα1-MOG-35-55 药物来解决未满足的需求并为 DR2 阴性提供覆盖。 MS 受试者补充 RTL1000 的更先进开发，用于 DR2 阳性 MS 受试者。