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

描述（由申请人提供）：虽然严重哮喘折磨相对较小比例的哮喘患者，但在美国，它影响数百万人。 尽管患有这种致残性疾病的患者有多种治疗方法，但部分由于病理生物学和临床异质性，许多患者的严重哮喘仍然难以控制。YKL-40是一种几丁质酶样蛋白，由人类几丁质酶-3-样-1（CHI 3L 1）基因编码。 我们的实验室发现，YKL-40在严重哮喘患者的循环和肺中升高。 此外，我们确定血液中的水平与气道中的YKL-40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，并可用于哮喘管理。我们还进行了血清YKL-40水平的全基因组关联研究，发现CHI 3L 1基因的变异，包括基因核心启动子区的单核苷酸多态性，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通过控制细胞凋亡、调节先天性和适应性免疫反应以及通过与IL-13受体α2（IL-13 R α2）结合介导肺中的修复反应，作为炎症和重塑的关键介质发挥作用。这导致促分裂原活化蛋白激酶（MAPK）、蛋白激酶B/AKT和Wnt/β-连环蛋白信号传导的活化，这是调节体内氧化损伤、凋亡、焦亡、炎性小体活化、抗菌反应、黑素瘤转移和TGF-β产生的级联事件。 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的治疗剂有可能成为严重哮喘的有效疗法。 在这项提案中，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。 在目标1（UH 2阶段）中，我们将开发针对YKL-40的人源化临床主要候选单克隆抗体，其抑制过敏性气道炎症，具有良好的安全性和药代动力学特征。在Aim 2/UH 3阶段，我们将与商业合作伙伴Covance一起进行ADME研究。在目标3中，我们将开发使用中间抗YKL-40单克隆抗体克隆的伴随诊断测试，用于测量游离和药物结合的YKL-40，以用于患者选择和治疗监测。 我们将准备提交用于治疗严重哮喘的人源化抗YKL-40抗体的研究性新药（IND）申请。 最终，YKL-40的靶向阻断将是astma医生治疗这种慢性严重疾病患者的重要补充，并且可以证明在炎症由YKL-40调节的其他疾病中有用。

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.