Preclinical Drug Approaches to Chronic GVHD Prevention and Treatment

慢性 GVHD 预防和治疗的临床前药物方法

• 批准号: 8881478
• 负责人: Bruce R Blazar
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881478
• 关键词: Acute; Agammaglobulinaemia tyrosine kinase; Allogenic; Antibodies; Antigens; B-Lymphocytes; BCL6 gene; Binding; Bortezomib; Bromodomain; Cell secretion; Cells; Cellular biology; Chromatin; Clinic; Clinical; Clinical Trials; Collagen; Collagen Type V; Data; Deposition; Disease; Drug Targeting; Employee Strikes; Epigenetic Process; Epithelial Cells; Fibrosis; Generations; Goals; Hematopoietic Stem Cell Transplantation; Immune; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulins; Injury; Inositol; Interleukin-2; Link; Lung; Malignant - descriptor; Methodology; Modeling; Morbidity - disease rate; Mus; Non-Malignant; Organ; Patients; Peptide antibodies; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Plasma Cells; Prevention; Process; Production; Proliferating; Proteasome Inhibitor; Quality of life; Reaction; Reagent; Relapse; Research Personnel; Rho-associated kinase; Signal Pathway; Signal Transduction; Site; Somatic Mutation; Source; Structure of germinal center of lymph node; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Agents; Tissues; Translations; Transplantation; Ubiquitin; Viral; Virus Diseases; antigen processing; base; body system; chronic graft versus host disease; clinically relevant; cytokine; drug testing; emt protein-tyrosine kinase; expectation; graft vs leukemia effect; improved; in vivo; inhibitor/antagonist; leukemia; macrophage; member; monocyte; mortality; mouse model; multicatalytic endopeptidase complex; nano; nanoparticle; novel; peptide V; pre-clinical; prevent; public health relevance; response; transcription factor; tumor; viral leukemia

 DESCRIPTION (provided by applicant): Our goal is to develop new drug or peptide therapies for chronic GVHD (cGVHD). We developed a new cGVHD model of multi-organ system injury and advanced the field by making the important observation that IgG deposition in tissues causes cGVHD. Germinal centers (GCs) are sites where B cells produce plasma cells (PCs) that secrete immunoglobulin (Ig). Our central hypothesis is that cGVHD results from a vigorous GC reaction, PC secretion of Ig with deposition in cGVHD organs causing collagen fibrosis, and these processes are treatable using clinically available drugs or as synthesized by Dr. Jay Bradner. These include inhibitors of Bruton's tyrosine kinase (BTK), B cell lymphoma-6 (BCL6), and inositol tetrakisphosphatase 3' kinase (ITPKb). Epigenetic modifiers, including a first-in-class bromodomain inhibitor drug, will be used to optimize BCL6 inhibitor efficacy. Given the importance of TFH IL-21 in cGVHD therapy, we selected a Rho-associated kinase 2 (ROCK2) inhibitor that blocks IL-21 production. The ubiquitin-proteasome system regulates cytokine production and antigen-processing; PCs are dependent upon proteasome function for survival. Bortezomib inhibits the constitutive proteasome and the immunoproteasome. Our preclinical data indicate that nano-encapsulation improves efficacy and will be further explored. Since constitutive proteasomes degrade and process many antigens, we will use a more selectively target the immunoproteasome, which regulates Ab production. Since cGVHD patients are highly susceptible to viral infections yet benefit from anti- leukemia effects, we will test our top agent for effects on anti-viral and -tumor responses in cGVHD mice as a prelude to clinical trials in cGVHD. To curtail fibrogenic mechanisms, we will target monocytes/macrophage survival, inhibit the production of or response to TGFb. We will build upon our striking data that lung fibrosis and collagen type V (col V) deposition can be prevented by in vivo tolerization with a collagen V peptide. Aim 1: GC B cells & PCs are critical targets for ameliorating cGVHD. We will test the hypotheses that key transcription factors and signaling pathways critical for GC and PC generation will prevent cGVHD (1A). We will test nanoparticle delivery and selectively targeting the immunoproteasome in PCs (1B). Aim 2. TGFb release by donor macrophages results in collagen deposition and fibrosis. We will test the hypothesis that a FcR+ cells are activated by IgG to release TGFb that induces col V in fibrotic organs (2A). We will test the hypothesis that col V peptide-induced tolerization can suppress lung fibrosis via TGFb effects and col V responses (2B). cGVHD therapeutic agents will permit effective anti-viral and GVL responses. We hypothesize that GVL (3A) and anti-viral (3B) responses will be retained with preferred agents from aims 1,2. Strengths include importance of new drug therapies for cGVHD, unique mice and reagents for clinical trials, a strong medicinal chemistry consortium, and strong investigators with expertise in B cell biology and fibrosis.

 描述（由申请人提供）：我们的目标是开发治疗慢性 GVHD（cGVHD）的新药或肽疗法。我们开发了一种新的多器官系统损伤的 cGVHD 模型，并通过组织中 IgG 沉积导致 cGVHD 的重要观察，推进了该领域的发展。生发中心 (GC) 是 B 细胞产生分泌免疫球蛋白 (Ig) 的浆细胞 (PC) 的场所。我们的中心假设是，cGVHD 是由剧烈的 GC 反应、PC 分泌 Ig 以及沉积在 cGVHD 器官中导致胶原纤维化引起的，并且这些过程可以使用临床可用的药物或由 Jay Bradner 博士合成的药物进行治疗。这些包括布鲁顿酪氨酸激酶 (BTK)、B 细胞淋巴瘤 6 (BCL6) 和肌醇四磷酸酶 3' 激酶 (ITPKb) 的抑制剂。表观遗传修饰剂，包括一流的溴结构域抑制剂药物，将用于优化 BCL6 抑制剂的功效。鉴于 TFH IL-21 在 cGVHD 治疗中的重要性，我们选择了一种 Rho 相关激酶 2 (ROCK2) 抑制剂来阻断 IL-21 的产生。泛素-蛋白酶体系统调节细胞因子的产生和抗原加工； PC 的生存依赖于蛋白酶体功能。硼替佐米抑制组成型蛋白酶体和免疫蛋白酶体。我们的临床前数据表明，纳米封装可以提高功效，并将得到进一步探索。由于组成型蛋白酶体降解和加工许多抗原，我们将使用更有选择性的靶向免疫蛋白酶体，它调节抗体的产生。由于 cGVHD 患者对病毒感染高度敏感，但仍能从抗白血病作用中获益，因此我们将测试我们的顶级药物对 cGVHD 小鼠的抗病毒和肿瘤反应的影响，作为 cGVHD 临床试验的前奏。为了减少纤维化机制，我们将针对单核细胞/巨噬细胞的存活，抑制 TGFb 的产生或反应。我们将基于我们的惊人数据，即通过使用 V 型胶原蛋白肽进行体内耐受可以预防肺纤维化和 V 型胶原蛋白 (col V) 沉积。目标 1：GC B 细胞和 PC 是改善 cGVHD 的关键靶标。我们将测试以下假设：对 GC 和 PC 生成至关重要的关键转录因子和信号通路将预防 cGVHD (1A)。我们将测试纳米颗粒的递送并选择性地靶向 PC 中的免疫蛋白酶体 (1B)。目标 2. 供体巨噬细胞释放 TGFb 导致胶原沉积和纤维化。我们将测试以下假设：FcR+ 细胞被 IgG 激活以释放 TGFb，从而在纤维化器官中诱导 col V (2A)。我们将检验这一假设：col V 肽诱导的耐受可以通过 TGFb 效应和 col V 反应抑制肺纤维化 (2B)。 cGVHD 治疗剂将产生有效的抗病毒和 GVL 反应。我们假设目标 1,2 中的首选药物将保留 GVL (3A) 和抗病毒 (3B) 反应。优势包括针对 cGVHD 的新药物疗法的重要性、用于临床试验的独特小鼠和试剂、强大的药物化学联盟以及在 B 细胞生物学和纤维化方面拥有专业知识的强大研究人员。