Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain

用于治疗化疗引起的周围神经性疼痛的治疗性抗体

基本信息

批准号：
10401479
负责人：
Andrea Grace Hohmann
金额：
$ 106.31万
依托单位：
ABALONE BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401479
关键词：
Adverse reactions Agonist Animal Model Animals Anti Inflammatory Analgesics Antibodies Appearance Astrocytes Behavior Binding Biochemical Biological Assay Blood Blood - brain barrier anatomy Blood Cell Count Breast Cancer Patient CNR1 gene CNR2 gene Cancer Patient Cell Culture Techniques Cells Chemotherapy-induced peripheral neuropathy Clinical Clinical Trials Cognitive Color Cyclic AMP Data Development Dose Drug or chemical Tissue Distribution Engineering Enzymes Fc Receptor Fiber Freezing Funding Glial Fibrillary Acidic Protein Goals Half-Life Health Care Costs Histology Immune In Vitro Inflammation Inflammatory Interleukin-10 Interleukin-6 Kidney Lead Liver Measures Mediating Microglia Modeling Motor Skills Mus Neurologic Neuronal Injury Neurons Neuropathy Opioid Organ Organ Weight Paclitaxel Pain Patients Peripheral Pharmaceutical Preparations Phase Prevention Preventive Quality of life Reducing Agents Risk Rodent Model Safety Serum Serum Markers Shapes Skin Small Business Innovation Research Grant Spinal Cord Study models Symptoms TNF gene Technology Therapeutic Therapeutic antibodies Toxic effect Travel Variant Weight Yeasts abalone activating transcription factor 3 allodynia cell growth chemotherapeutic agent chemotherapy clinical candidate cytokine density design dimer dosage duloxetine falls first-in-human immunogenicity improved in vivo injured macrophage manufacturability meetings motor impairment mouse model nanobodies nerve damage off-label use pain behavior pain reduction painful neuropathy patient subsets pharmacokinetics and pharmacodynamics prevent prophylactic rational design receptor side effect small molecule taxane tumor

项目摘要

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is an often long-lasting neurological condition that arises frequently in cancer patients who receive broadly used chemotherapies such as taxanes. CIPN causes abnormal pain and other symptoms that can limit chemotherapy dosage and significantly impact quality of life for years. There are no drugs that prevent CIPN or treat it well. Duloxetine is the only clinically proven efficacious pain- reducing agent, though it can cause significant side effects and its efficacy limited to a subset of patients. Opioids are used off-label, but also carry serious side effects. Thus, there is a critical unmet need for drugs that safely and effectively treat or prevent CIPN. Peripheral Cannabinoid 2 receptors (CB2) are a promising target for CIPN treatment. CB2 is constitutively expressed on inflammatory immune cells and induced in peripheral neurons in neuropathic conditions. Its activation has powerful neuroprotective, anti-inflammatory, and analgesic effects. Rodent models of CIPN show that small molecule CB2 agonists alleviate neuropathic pain behavior, and when administered prophylactically suppress CIPN both during dosing and for 100 days after. Several companies have developed small molecule CB2 agonists that, unfortunately, are rapidly cleared, penetrate the blood-brain barrier and/or have off-target effects (notably cognitive ones) mediated by the CB1 receptor. Abalone Bio used its proprietary Functional Antibody Selection Technology (FAST) to isolate a selective CB2-activating nanobody (VHH), which we converted into a VHH-Fc fusion lead antibody, ABt140, for in vivo studies. Phase I SBIR results show that ABt140 rapidly and durably reversed allodynia in mice with CIPN. In this Phase II SBIR project, Abalone Bio will first improve ABt140’s immunogenicity and manufacturability by rational engineering, and then the FAST platform will be used to increase its potency to select durable agonists from millions of computationally- designed variants. We will select 1 lead and at least 2 alternates using in vitro and in vivo assays. Using the paclitaxel CIPN mouse model, we will assess the lead’s ability to prevent CIPN development, reduce in nerve damage and inflammation, show no impairment of motor skills, and not affect chemotherapy’s anti-tumor efficacy. Finally, we will determine the lead antibody’s half-life and tissue distribution in mice, and using blood markers and organs appearance and weight, we will assess its toxicity at high doses. Successful completion of these aims will de-risk the project sufficiently to advance Abalone’s antibody drug to IND-enabling studies and eventually first in human trials for painful CIPN. Abalone’s drug may also have broad utility for other neuropathic pains and inflammatory conditions.

抽象的化疗引起的周围神经病变 (CIPN) 是一种通常长期持续的神经系统疾病，在接受广泛使用的化疗（如紫杉烷）的癌症患者中，经常会导致异常。疼痛和其他症状可能会限制化疗剂量并显着影响多年的生活质量。没有药物可以预防 CIPN 或有效治疗 CIPN，度洛西汀是唯一经临床证明有效的止痛药物。还原剂，尽管它可能会引起显着的副作用，并且其功效仅限于阿片类药物的一部分患者。药物在说明书外使用，但也具有严重的副作用，因此，对安全药物的需求亟待满足。并有效治疗或预防 CIPN 外周大麻素 2 受体 (CB2) 是 CIPN 的一个有前景的靶点。 CB2 在炎症免疫细胞上持续表达，并在周围神经元中被诱导。它的激活具有强大的神经保护、抗炎和镇痛作用。 CIPN 啮齿动物模型表明，小分子 CB2 激动剂可减轻神经性疼痛行为，并且当一些公司在给药期间和给药后 100 天内预防性抑制 CIPN。开发了小分子 CB2 激动剂，不幸的是，它会被迅速清除，穿透血脑屏障和/或具有由 CB1 受体介导的脱靶效应（尤其是认知效应）。专有的功能性抗体选择技术 (FAST)，用于分离选择性 CB2 激活纳米抗体 (VHH)，我们将其转化为 VHH-Fc 融合先导抗体 ABt140，用于体内 I 期 SBIR 结果。表明 ABt140 可以快速、持久地逆转 CIPN 小鼠的异常性疼痛。在这个 II 期 SBIR 项目中， Abalone Bio将首先通过合理工程提高ABt140的免疫原性和可制造性，然后 FAST 平台将用于增强其从数百万计算中选择持久激动剂的效力我们将使用体外和体内试验选择 1 个先导物和至少 2 个替代物。紫杉醇 CIPN 小鼠模型，我们将评估导线预防 CIPN 发展、减少神经损伤的能力炎症和炎症，不显示运动技能损伤，不影响化疗抗肿瘤最后，我们将使用血液确定先导抗体在小鼠中的半衰期和组织分布。标记物和器官外观和重量，我们将成功完成高剂量的毒性评估。这些目标将充分降低该项目的风险，以将 Abalone 的抗体药物推进 IND 支持的研究和最终，鲍鱼的药物首次在人体试验中用于治疗疼痛性 CIPN，也可能对其他神经病有广泛的用途。疼痛和炎症。