Development of A Dual Chemokine CCL2/CCL5 Neutralizing Single-domainAntibody for Treating Non-alcoholic Steatohepatitis

双趋化因子 CCL2/CCL5 中和单域抗体的开发用于治疗非酒精性脂肪性肝炎

• 批准号: 10761039
• 负责人: Xiang Gao
• 金额: $ 36.14万
• 依托单位: ONCOTRAP, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761039
• 关键词: Ablation; Acceleration; Adult; Affinity; Animals; Anti-Inflammatory Agents; Antibodies; Antiinflammatory Effect; Binding; Biological; Biological Response Modifier Therapy; Bispecific Antibodies; Bone Marrow; CCL2 gene; CCR5 gene; Cell Proliferation; Cirrhosis; Clinical; Complex; Data; Developed Countries; Development; Diabetes Mellitus; Diagnosis; Directed Molecular Evolution; Endothelial Cells; Engineering; Ensure; Epitopes; Erinaceidae; Excision; FDA approved; Failure; Fatty Liver; Fibrosis; GAG Gene; Half-Life; Hepatic Fibrogenesis; Human; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Investigation; Kupffer Cells; Lead; Left; Life Style; Ligand Binding; Ligands; Link; Liver; Liver Fibrosis; Liver diseases; Macrophage; Mediating; Medical; Metabolic Clearance Rate; Modeling; Mus; Mutation; Obesity; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Prevalence; Primary carcinoma of the liver cells; Property; RANTES; Recycling; Resolution; Role; Series; Serum; Signal Pathway; Signal Transduction; Site; Small Business Innovation Research Grant; Specificity; Steatohepatitis; Surface; Testing; Therapeutic antibodies; Translating; United States; Variant; Work; Yeasts; antagonist; bench to bedside; beta-Chemokines; biophysical properties; chemokine; chemokine receptor; cytokine; dosage; drug action; drug clearance; experimental study; hepatocyte injury; improved; in vivo; innovation; liver inflammation; liver injury; liver transplantation; monocyte; mouse model; nanobodies; neutralizing antibody; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; pharmacokinetics and pharmacodynamics; pharmacologic; phase 2 study; phase III trial; preclinical evaluation; primary endpoint; receptor; recruit; response; small molecule; smoothened signaling pathway; success

Abstract Nonalcoholic fatty liver disease (NAFLD) incidence is rapidly rising, in link with obesity and diabetes, and has become the most common cause of liver disease in developed countries. The prevalence of NAFLD is increasing steadily from 25% in 2018 to a projected 33.5% in 2030 globally. It is estimated approximately 20% of those NAFLD patients have non-alcoholic steatohepatitis (NASH). Without medical intervention, NASH patients will develop end-stage cirrhosis and even hepatocellular carcinoma. Unfortunately, there are no pharmacological agents available for treating NASH even though they are diagnosed at early stage. Patients have to adapt healthy life style to improve the situation, and such efforts are often in vain due to complex reasons. The only treatment option left is the resection, ablation or liver transplantation if diagnosed at early stage. In a response to this urgent unmet need, we have developed a bispecific single domain antibody targeting both chemokines CCL2 and CCL5 simultaneously which are critical players in the pathogenesis of liver fibrosis. In a proof-of-concept study conducted in a STAM NASH model, we have demonstrated that our bispecific antibody OT-m225 was able to outperform a phase 3 staged NASH drug-cenicriviroc- with regard to anti-fibrotic and anti- inflammatory effects. In order to ensure the clinical success of this OT-225 bispecific antibody, we propose to generate a human version of OT-h225 under the guidance of data from the STAM mouse model. This is going to be carried out parallelly in two specific aims. In Aim 1, we will harness both the STAM and the MCD NASH mouse models to screen a lead OT-m225 candidate from a series of variants with different binding affinities toward mouse CCL2 and CCL5. The effect OT-m225 or its optimal variant in modulating Hedgehog signaling and in inhibiting HSCs activation will be assessed as a subcontract at Duke Liver Center. Meanwhile in aim 2, we will further engineer the optimal OT-m225 variant from Aim 1 by yeast surface display-based directed molecular evolution, aiming at developing a version of OT-h225 that potently neutralizes and displaces GAG- bound CCL2 and CCL5 in human NASH, paving the way for IND-enabling development. The success of this Phase I SBIR project will result in a unique human single domain antibody that will be further developed into an innovative, first-in-class therapeutic biologic for the treatment of human NAFLD and NASH. Phase II studies will focus on extensive mechanistic, anti-fibrotic efficacy, developability, and PK/PD studies for IND purpose.

抽象的 非酒精性脂肪肝 (NAFLD) 发病率迅速上升，与肥胖和糖尿病有关，并且 已成为发达国家肝病的最常见原因。 NAFLD 的患病率是 全球范围内的增长率从 2018 年的 25% 稳步增长到 2030 年预计的 33.5%。估计约为20% 的 NAFLD 患者患有非酒精性脂肪性肝炎 (NASH)。如果没有医疗干预，NASH 患者会发展为终末期肝硬化，甚至肝癌。不幸的是，没有 即使 NASH 是在早期诊断出来的，也可使用药物治疗。患者 必须采取健康的生活方式来改善这种情况，但由于复杂的原因，这种努力往往是徒劳的。 如果早期诊断，唯一的治疗选择是切除、消融或肝移植。在一个 为了满足这一迫切的未满足需求，我们开发了一种双特异性单域抗体 同时趋化因子 CCL2 和 CCL5 在肝纤维化的发病机制中起关键作用。在一个 在 STAM NASH 模型中进行的概念验证研究，我们已经证明我们的双特异性抗体 OT-m225 在抗纤维化和抗- 炎症作用。为了确保OT-225双特异性抗体的临床成功，我们建议 在 STAM 小鼠模型数据的指导下生成人类版本的 OT-h225。这是要 为两个具体目标同时进行。在目标 1 中，我们将利用 STAM 和 MCD NASH 小鼠模型从一系列具有不同结合亲和力的变体中筛选主要 OT-m225 候选物 针对小鼠 CCL2 和 CCL5。 OT-m225 或其最佳变体在调节 Hedgehog 信号传导中的作用 抑制 HSC 激活方面的研究将作为杜克肝脏中心的分包合同进行评估。同时在目标 2 中， 我们将通过基于酵母表面展示的定向进一步设计来自 Aim 1 的最佳 OT-m225 变体 分子进化，旨在开发一种 OT-h225 版本，可有效中和并取代 GAG- 在人类 NASH 中结合 CCL2 和 CCL5，为 IND 开发铺平道路。此次活动的成功 I 期 SBIR 项目将产生一种独特的人类单域抗体，该抗体将进一步开发为 用于治疗人类 NAFLD 和 NASH 的创新、一流的治疗生物制剂。第二阶段研究将 专注于广泛的机制、抗纤维化功效、可开发性和 IND 目的的 PK/PD 研究。