Development of Nav1.7 Monoclonal Antibodies for Treating Pain

开发用于治疗疼痛的 Nav1.7 单克隆抗体

• 批准号: 10318547
• 负责人: JOSEPH Benjamin RUCKER
• 金额: $ 47.48万
• 依托单位: INTEGRAL MOLECULAR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318547
• 关键词: Abbreviations; Address; Affect; Affinity; American; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Therapy; Binding; Biological Assay; Biological Availability; Biosensor; Blood - brain barrier anatomy; Cells; Clinic; Clinical Trials; Complex; Data; Development; Dose; Engineering; Environment; Epitopes; Family member; Generations; Genes; Goals; Health; Human; Immunization; Immunize; Industry; Ion Channel; Kinetics; Lead; Lidocaine; Lipids; Location; Measures; Medical; Membrane Potentials; Membrane Proteins; Molecular; Molecular Conformation; Monoclonal Antibodies; N-formylmethionylphenylalanine; Neurons; Opioid; Pain; Peripheral; Peripheral Nervous System Diseases; Phage Display; Pharmaceutical Preparations; Phase; Probability; Protein Engineering; Proteins; Public Health; Role; Serum; Small Business Innovation Research Grant; Sodium Channel; Specificity; Structure; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; TimeLine; Variant; addiction; arm; base; burden of illness; chronic pain; disability; disability burden; experience; gain of function mutation; heart function; humanized monoclonal antibodies; improved; loss of function mutation; non-opioid analgesic; novel; opioid epidemic; overexpression; pain relief; pain sensation; pain signal; patch clamp; preclinical study; receptor; response; risk minimization; small molecule inhibitor; small molecule therapeutics; therapeutic development; voltage

ABSTRACT Chronic pain is a significant medical problem, affecting over 50 million Americans and representing the largest cause of disability and disease burden globally. Current pain relief treatments rely heavily on opioid drugs, which are only partially effective and have a limited therapeutic window. Sustained use of opioids increases the probability of misuse and addiction, which has led to the current opioid epidemic. Development of efficacious, non-opioid analgesics could help mitigate this public health crisis and address a significant unmet medical need. The voltage-gated sodium ion channel Nav1.7 is one of the primary components involved in pain signal generation. Loss-of-function mutations in the gene encoding Nav1.7 (SCN9A) result in complete insensitivity to pain in humans. Conversely, gain-of-function mutations contribute to painful peripheral neuropathies. Small molecule inhibitors of Nav1.7, such as lidocaine, also validate the role of Nav1.7 in pain, but such molecules cannot be used systemically because they also non-specifically inhibit other sodium channels such as Nav1.5 (required for cardiac function). Despite the remarkable role of Nav1.7 in pain sensation, drugs that specifically block Nav1.7 have so far proven ineffective in clinical trials. Small molecule therapeutics lack channel subtype selectivity, and poor bioavailability has made effective dosing difficult in clinical trials. Monoclonal antibodies (MAbs) offer therapeutic advantages of improved specificity and bioavailability, but there are currently no good MAbs against Nav1.7. Inhibitory MAbs against ion channels such as Nav1.7 are extremely challenging to isolate because, unlike soluble proteins, ion channels form complex transmembrane structures, are toxic when overexpressed, and are difficult to purify away from their native lipid environment. Here we propose to develop Nav1.7 monoclonal antibodies for treating pain.

摘要 慢性疼痛是一个重大的医疗问题，影响超过5000万美国人，并代表了最大的 造成全球残疾和疾病负担。目前的疼痛缓解治疗严重依赖阿片类药物， 其仅部分有效并且具有有限的治疗窗。持续使用阿片类药物增加了 滥用和成瘾的可能性，导致目前的阿片类药物流行病。开发有效的， 非阿片类镇痛药可以帮助缓解这一公共卫生危机，并解决一个重大的未满足的医疗需求。 需要的电压门控钠离子通道Nav1.7是参与疼痛信号的主要成分之一 一代编码Nav1.7（SCN9A）的基因中的功能缺失突变导致对 人类的痛苦相反，功能获得性突变导致疼痛性周围神经病变。小 Nav1.7的分子抑制剂，如利多卡因，也证实了Nav1.7在疼痛中的作用，但这些分子 不能全身使用，因为它们也非特异性抑制其他钠通道，如Nav1.5 （心脏功能所需）。尽管Nav1.7在疼痛感觉中发挥了显著作用，但特异性抑制Nav1.7的药物 迄今为止，Nav1.7块在临床试验中被证明无效。小分子治疗缺乏通道亚型 选择性和差的生物利用度使得在临床试验中难以进行有效给药。单克隆抗体 单克隆抗体（MAb）提供了改善的特异性和生物利用度的治疗优势，但目前还没有良好的 针对Nav1.7的MAb。针对离子通道（如Nav1.7）的抑制性MAb对于抑制细胞内的细胞生长是极其具有挑战性的。 分离是因为与可溶性蛋白质不同，离子通道形成复杂跨膜结构，当 它们是过表达的，并且难以从它们的天然脂质环境中纯化。在这里，我们建议开发 用于治疗疼痛的Nav1.7单克隆抗体。