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

基本信息

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
项目类别：
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

项目摘要

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严重的医疗问题，影响超过 5000 万美国人，是最大的慢性疼痛全球残疾和疾病负担的原因。目前的止痛治疗严重依赖阿片类药物，这些药物仅部分有效且治疗窗有限。持续使用阿片类药物会增加滥用和成瘾的可能性，导致了当前阿片类药物的流行。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重大未满足的医疗问题需要。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) 的基因的功能丧失突变导致对人类的痛苦。相反，功能获得性突变会导致痛苦的周围神经病。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，但此类分子不能全身使用，因为它们还非特异性抑制其他钠通道，例如 Nav1.5 （心脏功能所需）。尽管 Nav1.7 在痛觉方面具有显着的作用，但专门针对 Nav1.7 的药物 block Nav1.7 迄今为止在临床试验中被证明无效。小分子疗法缺乏通道亚型选择性和较差的生物利用度使得临床试验中有效给药变得困难。单克隆抗体（MAb）具有提高特异性和生物利用度的治疗优势，但目前还没有好的治疗方法针对 Nav1.7 的 MAb。针对 Nav1.7 等离子通道的抑制性 MAb 极具挑战性分离，因为与可溶性蛋白质不同，离子通道形成复杂的跨膜结构，当过度表达，并且很难从其天然脂质环境中纯化出来。在这里我们建议开发用于治疗疼痛的 Nav1.7 单克隆抗体。