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，但在美国有数百万人受到影响。尽管有许多治疗方法可用于这种致残患者，但在许多患者中，严重哮喘仍然难以控制，部分原因是病理生物学和临床异质性。YKL-40是一种几丁质酶样蛋白，由人类几丁质酶-3-样-1(CHI3L1)基因编码。我们的实验室发现，YKL-40在一组重症哮喘患者的循环和肺组织中升高。此外，我们确定血液中的水平与YKL-40在气道中的表达、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亚组的生物标志物，并对哮喘治疗有用。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，影响血清YKL-40水平、哮喘患病率和肺功能。我们和其他人随后发现，YKL-40通过与IL-13受体α2(IL-13Rα2)结合，控制细胞凋亡，调节先天和获得性免疫反应，并介导肺内修复反应，从而发挥炎症和重塑的关键中介作用。这导致丝裂原激活的蛋白激酶(MAPK)、蛋白激酶B/AKT和Wnt/ç-catenin的激活--信号传递一连串的事件，调节体内的氧化剂损伤、细胞凋亡、下垂、炎性肌小体激活、抗菌反应、黑色素瘤转移和转化生长因子的产生。此外，多项研究表明，在基因敲除小鼠中抑制YKL-40或使用YKL-40抗体可以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的治疗性药物有可能成为治疗严重哮喘的有效药物。在这项提案中，我们在翻译研究、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的人源化单抗的临床前开发。在目标1，UH2阶段，我们将开发一种人源化的临床领先候选抗YKL-40单抗，该抗体具有良好的安全性和药代动力学特征，可抑制过敏性呼吸道炎症。在目标中 2/UH3阶段，我们将与Covance的商业合作伙伴一起进行ADME研究。在目标3中，我们将开发一种使用中间抗YKL-40单抗克隆的配套诊断试验，用于测量游离和药物结合的YKL-40，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抗体的研究新药(IND)申请。最终，靶向阻断YKL-40将成为Astma医生治疗这种慢性严重疾病患者的关键补充，并可能被证明对其他由YKL-40调节炎症的疾病有用。

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.