Pre-Clinical Development of a Novel Anti-YKL-40 Biologic to Treat Severe Asthma

描述（由申请人提供）：虽然严重哮喘患者的比例相对较小，但在美国，它影响着数百万人。尽管有许多治疗方法可用于患有这种致残疾病的患者，但由于病理生物学和临床异质性，许多患者仍然难以控制严重哮喘。YKL-40是人类几丁质酶-3- like -1 （CHI3L1）基因编码的几丁质酶样蛋白。我们的实验室发现，YKL-40在严重哮喘亚群的循环和肺中升高。此外，我们确定血液中YKL-40的水平与气道中YKL-40的表达、肺功能降低和病理性气道重塑相关。这些研究表明，YKL-40水平可以作为选择哮喘患者子集的生物标志物，并对哮喘管理有用。我们还进行了血清YKL-40水平的全基因组关联研究，发现CHI3L1基因的变异，包括该基因核心启动子区域的单核苷酸多态性，会影响血清YKL-40水平、哮喘患病率和肺功能。我们的研究小组和其他研究人员随后发现，YKL-40作为炎症和重塑的关键介质，通过与IL-13受体α2 （IL-13Rα2）结合来控制细胞凋亡，调节先天和适应性免疫反应，并介导肺中的修复反应。这导致丝裂原活化蛋白激酶（MAPK）、蛋白激酶B/AKT和Wnt/ß-catenin的激活，信号传导一系列事件，调节体内氧化损伤、细胞凋亡、焦亡、炎性体激活、抗菌反应、黑色素瘤转移和TGF-ß的产生。此外，多项研究表明，在敲除小鼠中抑制YKL-40或使用针对YKL-40的抗体可抑制哮喘动物模型中的炎症和IL-13转基因表达的下游。这些研究表明，针对YKL-40的治疗有可能成为严重哮喘的有效治疗方法。在本次提案中，我们在转化研究、基因组学、药物开发和免疫学方面的多学科团队将完成针对YKL-40的人源化单克隆抗体的临床前开发。在Aim 1， UH2期，我们将开发一种针对YKL-40的人源化临床先导候选单克隆抗体，该抗体具有良好的安全性和药代动力学特征，可抑制过敏性气道炎症。在目标中

DESCRIPTION (provided by applicant): Although severe asthma afflicts a relatively small percentage of individuals with asthma, it affects millions of individuals in the United States. Despite the numerous therapies available for patients with this disabling diseas, severe asthma remains difficult to control in many patients due in part to pathobiologc and clinical heterogeneity. YKL-40 is a chitinase-like protein that is encoded by the Chitinase-3-Like-1 (CHI3L1) gene in humans. Our laboratories discovered that YKL-40 is elevated in the circulation and lung of a subgroup of severe asthmatics. In addition, we determined that the levels in the blood correlate with YKL-40 expression in the airway, reduced lung function, and pathologic airway remodeling. These studies suggested that YKL-40 levels could serve as a biomarker for selecting a subset of patients with asthma and be useful for asthma management. We also conducted a genome wide association study of serum YKL-40 levels and discovered that variation in the CHI3L1 gene, including a single nucleotide polymorphism in the gene's core promoter region, influences serum YKL-40 levels, asthma prevalence, and lung function. Our group and others then discovered that YKL-40 functions as a critical mediator of inflammation and remodeling by controlling apoptosis, modulating innate and adaptive immune responses, and mediating repair responses in the lung via binding to IL-13 receptor α2 (IL-13Rα2). This leads to activation of mitogen-activated protein kinase (MAPK), protein kinase B/AKT, and Wnt/ß-catenin-signaling a cascade of events that regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-ß production in vivo. Furthermore, multiple studies have shown that inhibition of YKL-40 in knockout mice or using antibodies against YKL-40 inhibits inflammation in animal models of asthma and downstream of transgenic expression of IL-13. These studies demonstrate that a therapeutic against YKL-40 has the potential to be an effective therapy for severe asthma. In this proposal, our multidisciplinary team in translational research, genomics, drug development, and immunology will complete the pre-clinical development of humanized monoclonal antibodies against YKL-40. In Aim 1, the UH2 Phase, we will develop a humanized clinical lead candidate monoclonal antibody against YKL-40 that inhibits allergic airway inflammation with a favorable safety and, pharmacokinetic profiles. In the Aim 2/UH3 Phase, with a commercial partner Covance, we will conduct ADME studies. In Aim 3, we will develop a companion diagnostic test using intermediate anti- YKL-40 monoclonal antibodies clones for the measurement of free and drug-bound YKL-40 for patient selection and therapeutic monitoring. We will prepare to submit an Investigational New Drug (IND) application for a humanized anti-YKL-40 antibody for the treatment of severe asthma. Ultimately, targeted blockade of YKL-40 will be a critical addition to the astma physician's armamentarium to treat patients with this chronic severe disease and could prove useful in other disease where inflammation is modulated by YKL-40.