Therapeutic antibodies for treating liver fibrosis

用于治疗肝纤维化的治疗性抗体

基本信息

  • 批准号:
    10666671
  • 负责人:
  • 金额:
    $ 100万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

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, i.e., scar tissue that blocks the flow of blood through the liver, raising blood pressure and disturbing normal function. There are no approved drugs for fibrotic non-alcoholic steatohepatitis (NASH), which often progresses to cirrhosis, so patients are often left with “lifestyle modifications” that are difficult to sustain, and, at best, put patients in a race against disease progression. CB2 agonism is a promising mode of action for treating liver fibrosis/NASH. Small molecule agonists of the cannabinoid receptor CB2 have reduced liver fibrosis in several established animal models by inhibiting hepatic immune cells and hepatic stellate cells. However, small molecule CB2 agonists have drawbacks, including cross-reactivity with pro-inflammatory/pro-fibrotic CB1 receptors in immune cells and psychotropic CB1 receptors in the CNS, and rapid elimination from the body. Therefore, a CB2 agonist antibody (Ab) that is highly specific for CB2 over CB1, restricted from passing the blood-brain barrier into the CNS, and is long-lived would be an ideal drug for liver fibrosis. Unlike small molecules, which often show liver toxicities, Ab drugs have excellent safety track records in treating chronic diseases. Abalone Bio used its proprietary antibody discovery platform to isolate a selective CB2-activating nanobody (VHH), ABt101. In Phase I, ABt101 was successfully modified and reformatted into a VHH-Fc fusion antibody (ABt140) to increase its stability and in vivo half-life. Feasibility of the CB2 Ab agonist for liver fibrosis was demonstrated using two complementary in vivo models. In this Phase II SBIR project, Abalone Bio will improve ABt140’s immunogenicity an manufacturability by rational engineering, and increase its potency by selecting stronger agonists from millions of computationally designed variants using Abalone Bio’s proprietary functional Ab selection platform. Then, the selected candidate Ab will be manufactured according to Good Manufacturing Practices (GMP) standards. Progress made in parallel to this project in advancing the CB2 agonist Ab for another indication will cover remaining manufacturing development and preclinical testing (i.e., IND-enabling tox studies). The proposed GMP production run will produce clinical drug substance (DS) supply at 500L bioreactor scale, generating sufficient DS for phase I clinical studies in liver fibrosis. In parallel, the candidate Ab will be tested for efficacy in two of the most relevant disease models of NASH and fibrosis. The Ab will be applied to liver slices to understand the mechanism of action of the CB2 agonist in the context of endogenous cell-cell interactions. The FAT-NASH animal model will validate the functional anti-fibrotic activity of the CB2 agonist at a lower dose level of the optimized antibody, and the TAA model will test the activity of the CB2 agonist in a model of severe fibrosis. These studies will generate material for clinical studies and help select the most suitable patient groups for treatment with the CB2 agonist antibody.
摘要 肝硬化是美国十大主要死亡原因之一,每种死亡人数超过35,000人 年肝硬化的主要潜在原因是与肝纤维化相关的肝损伤,即,疤痕组织 血液通过肝脏的流动,使血压升高,干扰正常功能。没有批准的 纤维化非酒精性脂肪性肝炎(NASH)的药物,通常进展为肝硬化,因此患者通常 留下难以维持的“生活方式改变”,最好的情况是,让患者与疾病赛跑 进展CB 2激动是治疗肝纤维化/NASH的有前景的作用模式。小分子激动剂 大麻素受体CB 2通过抑制多种已建立的动物模型来减少肝纤维化 肝免疫细胞和肝星状细胞。然而,小分子CB 2激动剂具有缺点, 包括与免疫细胞中的促炎/促纤维化CB 1受体和精神CB 1的交叉反应性, 中枢神经系统中的受体,并迅速从体内消除。因此,高度表达CB 2激动剂抗体(Ab), 对CB 2的特异性超过CB 1,限制通过血脑屏障进入CNS,并且寿命长, 是治疗肝纤维化的理想药物。与经常显示肝毒性的小分子药物不同,Ab药物具有 在治疗慢性病方面有着良好的安全记录。鲍鱼生物利用其专有的抗体发现 平台分离选择性CB 2活化纳米抗体(VHH)ABt 101。在第一阶段,ABt 101成功地 修饰并重新格式化成VHH-Fc融合抗体(ABt 140)以增加其稳定性和体内半衰期。 使用两种互补的体内模型证明了CB 2 Ab激动剂用于肝纤维化的可行性。 在这个II期SBIR项目中,Abalone Bio将通过合理的方法提高ABt 140的免疫原性和可制造性。 工程,并通过从数百万个计算设计的激动剂中选择更强的激动剂来提高其效力 使用Abalone Bio专有的功能性抗体选择平台进行变体。然后,所选择的候选Ab将 根据良好生产规范(GMP)标准生产。与此同时取得的进展 推进CB 2激动剂Ab用于另一种适应症的项目将涵盖剩余的生产开发 和临床前测试(即,IND启动毒性研究)。拟定的GMP生产运行将产生临床 以500 L生物反应器规模供应原料药(DS),生成足够的DS用于肝脏I期临床研究 纤维化同时,将在两种最相关的疾病模型中测试候选Ab的功效, NASH和纤维化。将Ab应用于肝脏切片,以了解CB 2的作用机制 在内源性细胞-细胞相互作用的背景下,激动剂。FAT-NASH动物模型将验证 CB 2激动剂在优化抗体的较低剂量水平下的功能性抗纤维化活性,和TAA 模型将测试CB 2激动剂在严重纤维化模型中的活性。这些研究将产生材料 用于临床研究,并帮助选择最适合CB 2激动剂抗体治疗的患者群体。

项目成果

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SCOTT L. FRIEDMAN其他文献

SCOTT L. FRIEDMAN的其他文献

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{{ truncateString('SCOTT L. FRIEDMAN', 18)}}的其他基金

Training Program in Investigative Gastroenterology and Hepatology
胃肠病学和肝病学研究培训计划
  • 批准号:
    10628499
  • 财政年份:
    2023
  • 资助金额:
    $ 100万
  • 项目类别:
Hepatic stellate cells in NASH fibrosis and HCC
NASH 纤维化和 HCC 中的肝星状细胞
  • 批准号:
    10350710
  • 财政年份:
    2021
  • 资助金额:
    $ 100万
  • 项目类别:
Hepatic stellate cells in NASH fibrosis and HCC
NASH 纤维化和 HCC 中的肝星状细胞
  • 批准号:
    10182514
  • 财政年份:
    2021
  • 资助金额:
    $ 100万
  • 项目类别:
Hepatic stellate cells in NASH fibrosis and HCC
NASH 纤维化和 HCC 中的肝星状细胞
  • 批准号:
    10597033
  • 财政年份:
    2021
  • 资助金额:
    $ 100万
  • 项目类别:
Therapeutic antibodies for treating liver fibrosis
用于治疗肝纤维化的治疗性抗体
  • 批准号:
    10547688
  • 财政年份:
    2020
  • 资助金额:
    $ 100万
  • 项目类别:
Therapeutic antibodies for treating liver fibrosis
用于治疗肝纤维化的治疗性抗体
  • 批准号:
    10011650
  • 财政年份:
    2020
  • 资助金额:
    $ 100万
  • 项目类别:
Liver Cancer (LC) (Project-003)
肝癌 (LC)(项目-003)
  • 批准号:
    8932193
  • 财政年份:
    2015
  • 资助金额:
    $ 100万
  • 项目类别:
Autophagy during hepatic stellate cell activation in alcoholic liver injury
酒精性肝损伤肝星状细胞激活过程中的自噬
  • 批准号:
    8334729
  • 财政年份:
    2011
  • 资助金额:
    $ 100万
  • 项目类别:
Autophagy during hepatic stellate cell activation in alcoholic liver injury
酒精性肝损伤肝星状细胞激活过程中的自噬
  • 批准号:
    8504895
  • 财政年份:
    2011
  • 资助金额:
    $ 100万
  • 项目类别:
Autophagy during hepatic stellate cell activation in alcoholic liver injury
酒精性肝损伤肝星状细胞激活过程中的自噬
  • 批准号:
    8705327
  • 财政年份:
    2011
  • 资助金额:
    $ 100万
  • 项目类别:

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  • 财政年份:
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