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.

抽象的 慢性疼痛是一个重大的医学问题，影响了超过5000万美国人，代表了最大的人 全球残疾和疾病负担的原因。当前的缓解疼痛治疗严重依赖阿片类药物， 仅部分有效，并且具有有限的治疗窗口。持续使用阿片类药物会增加 滥用和成瘾的可能性，这导致了当前的阿片类药物流行。开发有效的， 非阿片类镇痛药可以帮助减轻这一公共卫生危机，并解决重大的未得到医学 需要。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）的基因中功能丧失突变导致对完全不敏感 人类的疼痛。相反，功能收益突变有助于疼痛的周围神经病。小的 NAV1.7的分子抑制剂，例如利多卡因，也验证了NAV1.7在疼痛中的作用，但是这种分子 无法系统地使用，因为它们也非特异性抑制其他钠通道，例如NAV1.5 （心脏功能需要）。尽管NAV1.7在疼痛感觉中的作用显着，但专门的药物 迄今为止，Block NAV1.7在临床试验中已证明无效。小分子疗法缺乏通道亚型 在临床试验中，选择性和生物利用度差使有效的给药变得困难。单克隆抗体 （mab）提供改善特异性和生物利用度的治疗优势，但目前没有好 对抗NAV1.7的mAb。抑制性mAb对诸如NAV1.7之类的离子频道的mAb对 分离株，因为与可溶性蛋白不同，离子通道形成复杂的跨膜结构，当 过表达，很难净化其本地脂质环境。在这里我们建议发展 NAV1.7单克隆抗体治疗疼痛。