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.

摘要