Preclinical Drug Approaches to Chronic GVHD Prevention and Treatment

 描述（由申请人提供）：我们的目标是开发用于慢性GVHD（cGVHD）的新药物或肽疗法。我们开发了一种新的多器官系统损伤的cGVHD模型，并通过在组织中IgG沉积导致cGVHD的重要观察而推进了该领域。生殖中心（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由剧烈的GC反应、PC分泌IG并沉积在cGVHD器官中引起胶原纤维化引起，并且这些过程可使用临床可用的药物或如Jay布拉德纳博士所合成的那样治疗。这些包括布鲁顿酪氨酸激酶（BTK）、B细胞淋巴瘤-6（BCL 6）和肌醇四磷酸酶3'激酶（ITPK B）的抑制剂。表观遗传修饰剂，包括一流的布罗莫结构域抑制剂药物，将用于优化BCL 6抑制剂的功效。鉴于TFH IL-21在cGVHD治疗中的重要性，我们选择了阻断IL-21产生的Rho相关激酶2（ROCK 2）抑制剂。泛素-蛋白酶体系统调节细胞因子的产生和抗原加工; PC的存活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，纳米封装提高了疗效，并将进一步探索。由于组成型蛋白酶体降解和处理许多抗原，我们将使用一个更有选择性的目标免疫蛋白酶体，调节抗体的生产。由于cGVHD患者对病毒感染高度敏感，但受益于抗白血病作用，因此我们将测试我们的顶级药剂对cGVHD小鼠中的抗病毒和抗肿瘤反应的作用，作为cGVHD临床试验的前奏。为了减少纤维化机制，我们将靶向单核细胞/巨噬细胞存活，抑制TGF β的产生或对TGF β的反应。我们将建立在我们的惊人的数据，肺纤维化和胶原V型（col V）的沉积可以防止在体内耐受与胶原V肽。目的1：GC B细胞和PC是改善cGVHD的关键靶点。我们将检验对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的假设（1A）。我们将测试纳米颗粒递送和选择性靶向PC中的免疫蛋白酶体（1B）。目标2.供体巨噬细胞释放TGF β导致胶原沉积和纤维化。我们将检验FcR+细胞被IgG激活以释放诱导纤维化器官中的col V的TGFb的假设（2A）。我们将检验col V肽诱导的耐受化可通过TGF β效应和col V应答抑制肺纤维化的假设（2B）。cGVHD治疗剂将允许有效的抗病毒和GVL应答。我们假设GVL（3A）和抗病毒（3B）反应将保留与目标1，2的首选药物。优势包括cGVHD新药治疗的重要性，独特的小鼠和临床试验试剂，强大的药物化学联盟，以及在B细胞生物学和纤维化方面具有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.