Therapeutic antibodies for treating liver fibrosis

摘要 肝硬化是美国十大死亡原因之一，死亡人数超过35，000人 每年.肝硬化的一个主要潜在原因是与肝纤维化相关的肝损伤;肝纤维化的病理改变是肝硬化的病理基础。 肝硬化的指征是疤痕组织的发展，其取代了正常的实质。疤痕组织 阻塞血液通过肝脏的流动，升高血压并干扰正常功能。 目前治疗纤维化的药物并不总是有效的。患者通常会留下“生活方式的改变”， 很难维持，而且，充其量，使患者与疾病进展赛跑。小分子激动剂 大麻素受体CB 2的抑制剂在几种已建立的动物模型中减少了肝纤维化。CB2 激动剂通过抑制肝免疫细胞和肝星状细胞来实现这一目标。CB 2激动是一种 治疗肝纤维化的有前景的作用模式。然而，小分子CB 2激动剂具有 削弱其有效性和安全性的缺点，包括与CB 1的交叉反应性，穿过血液， 脑屏障和交叉激活CB 1，导致大麻素的不良认知作用和快速 从身体中消除。一种高特异性CB 2激动剂抗体，其寿命长且仅限于 外周组织将是测试CB 2激动作用模式的理想药物。 鲍鱼生物提出3项旨在测试使用CB 2激动剂抗体药物治疗肝纤维化的可行性。 (1)工程师，生产，表征CB 2激动剂抗体。将制备鉴定命中的VHH-Fc版本， 使用多种基于非肝细胞的体外测定来表征。(2)评估CB 2激动剂抗体的作用 在肝细胞上。在该目的中，来自目的1的抗体将用于表征原发性肝纤维化中的抗纤维化作用。 肝细胞和体外稳定的肝细胞系。这些数据将在标准细胞系中建立受体药理学的桥梁 与来自Aim 3的体内数据相结合，可以验证和扩展纤维化的生物标志物。(3)评估抗纤维化作用 CB 2激动剂抗体在肝纤维化体内模型中的作用（与领先的肝纤维化专家和联盟 PI，Scott Friedman博士）。该目的将测试使用CB 2激动剂治疗肝纤维化的可行性。 通过测量抗体对血液标志物，胶原蛋白水平， 组织病理学指标和基因表达。 I期项目的成功将导致一种安全有效的肝纤维化药物，增加科学性 了解肝脏疾病，并定义非侵入性生物标志物以监测疾病进展。二期 （包括IND使能研究）将涉及选择和优化先导抗体，重点是良好的 临床和生产属性。这项研究将使鲍鱼生物扩大其CB 2的影响， 抗体激动剂药物用于涉及纤维化和炎症的其它疾病，例如，皮肤和肺部疾病， 硬皮病和特发性肺纤维化

Abstract Cirrhosis of the liver is among the top ten leading causes of death in the US, with more than 35,000 deaths each year. A major underlying cause of cirrhosis is liver injury associated with liver fibrosis; the pathological indication of cirrhosis is the development of scar tissue that replaces normal parenchyma. The scar tissue blocks the flow of blood through the liver, raising blood pressure and disturbing normal function. Current drugs that treat fibrosis are not always effective. Patients are often left with “lifestyle modifications” that are difficult to sustain, and, at best, put patients in a race against disease progression. Small molecule agonists of the cannabinoid receptor CB2 have reduced liver fibrosis in several established animal models. CB2 agonists achieve this by inhibiting hepatic immune cells and hepatic stellate cells. CB2 agonism is a promising mode of action for treating liver fibrosis. However, small molecule CB2 agonists have drawbacks that undercut their effectiveness and safety, including cross-reactivity with CB1, crossing the blood- brain barrier and cross-activating CB1, causing the adverse cognitive effects of cannabinoids and rapid elimination from the body. A highly specific CB2 agonist antibody that is long-lived and restricted to peripheral tissues would be an ideal drug to test the CB2 agonism mode of action. Abalone Bio proposes 3 aims to test the feasibility of using CB2 agonist antibody drugs to treat liver fibrosis. (1) Engineer, produce, characterize CB2 agonist antibodies. VHH-Fc versions of identified hits will be made and characterized using multiple non-liver in vitro cell-based assays. (2) Assess effects of CB2 agonist antibodies on liver cells. In this aim, the antibodies from Aim 1 will be used to characterize anti-fibrotic effects in primary liver cells and stable liver cell lines in vitro. The data will bridge receptor pharmacology in standard cell lines with in vivo data from Aim 3 and can validate and expand biomarkers for fibrosis. (3) Assess anti-fibrotic effects of a CB2 agonist antibody in an in vivo model of liver fibrosis (with leading liver fibrosis expert and Consortium PI, Dr. Scott Friedman). This aim will test the feasibility of using CB2 agonism to treat liver fibrosis in thioacetamide rat models by measuring the effects of the antibody on blood markers, collagen levels, histopathology metrics, and gene expression. Success in the Phase I project will lead to a safe and effective drug for liver fibrosis, increase scientific understanding of liver disease, and define non-invasive biomarkers to monitor disease progression. Phase II (including IND-enabling studies) will involve selecting and optimizing a lead antibody, with a focus on good clinical and manufacturing attributes. This research will enable Abalone Bio to expand the impact of its CB2 antibody agonist drugs to other diseases involving fibrosis and inflammation, e.g., skin and lung diseases such as scleroderma and idiopathic pulmonary fibrosis.