Preclinical Drug Approaches to Chronic GVHD Prevention and Treatment

 描述(申请人提供)：我们的目标是开发治疗慢性移植物抗宿主病(CGVHD)的新药或多肽疗法。我们建立了一个新的多器官系统损伤的cGVHD模型，并通过重要的观察到组织中的免疫球蛋白沉积导致了cGVHD，从而推动了该领域的发展。生发中心(GC)是B细胞产生浆细胞(PC)分泌免疫球蛋白(Ig)的场所。我们的中心假设是cGVHD是由于强烈的GC反应，PC分泌Ig并沉积在cGVHD器官中导致胶原纤维化，这些过程可以使用临床上可用的药物或Jay Bradner博士合成的药物进行治疗。这些药物包括布鲁顿酪氨酸激酶(BTK)、B细胞淋巴瘤-6(BCL6)和肌醇四氢磷酸酶3‘激酶(ITPKb)的抑制剂。表观遗传修饰剂，包括一种一流的溴域抑制剂药物，将被用于优化BCL6抑制剂的疗效。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的处理；PC依赖蛋白酶体的功能生存。Bortezomib抑制构成蛋白酶体和免疫蛋白酶体。我们的临床前数据表明，纳米胶囊可以提高疗效，并将得到进一步的探索。由于构成蛋白酶体降解和处理许多抗原，我们将使用更有选择性的靶标免疫蛋白酶体，它调节抗体的产生。由于cGVHD患者对病毒感染高度敏感，但却受益于抗白血病作用，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。为了减少纤维化的发生机制，我们将以单核/巨噬细胞存活为目标，抑制TGFb的产生或反应。我们将建立在我们惊人的数据的基础上，肺纤维化和V型胶原(COLV)沉积可以通过体内耐受性V型胶原多肽来预防。目的1：GC B细胞和PC是改善慢性移植物抗宿主病的关键靶点。我们将测试对GC和PC生成至关重要的关键转录因子和信号通路将防止cGVHD的假设(1A)。我们将测试纳米颗粒的传递和选择性地靶向PC中的免疫蛋白酶体(1B)。目的2.供体巨噬细胞释放TGFb可导致胶原沉积和纤维化。我们将检验这样一种假设，即FCR细胞被免疫球蛋白激活，释放TGFb，从而在纤维化器官中诱导胶原V(2A)。我们将通过TGFb效应和ColV反应来验证ColV肽诱导的耐受可以抑制肺纤维化的假说(2B)。CGVHD治疗剂将允许有效的抗病毒和GVL反应。我们假设GVL(3A)和抗病毒(3B)反应将与AIMS 1，2的首选药物一起保留。优势包括cGVHD新药疗法的重要性，独特的小鼠和临床试验试剂，强大的药物化学联盟，以及具有B细胞生物学和纤维化专业知识的强大研究人员。

 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.