Development of therapeutic antibodies to target sodium channels involved in pain signaling

开发针对参与疼痛信号传导的钠通道的治疗性抗体

• 批准号: 10453929
• 负责人: HEIKE WULFF
• 金额: $ 158.7万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453929
• 关键词: Action Potentials; Afferent Neurons; Antibodies; Antigen Targeting; Antigens; Applications Grants; Binding; Biological Products; Biological Response Modifier Therapy; Biology; Biometry; C Fiber; Chemotherapy-induced peripheral neuropathy; Circular Dichroism; Clinical; Computer software; Data; Development; Electrophysiology (science); Elements; Epitopes; Escherichia coli; Evaluation; FDA approved; Feedback; Generations; Genetic study; Goals; Grant; Human; Human Genetics; Immunize; Immunoglobulin G; Interdisciplinary Study; Intrathecal Injections; Ion Channel; Kinetics; Llama; Manuals; Mediator of activation protein; Modeling; Molecular Conformation; Molecular Probes; Molecular Target; Monoclonal Antibodies; Mus; Neurosciences; Nociceptors; Pain; Pain management; Peptides; Pharmacology; Phase; Positioning Attribute; Pre-Clinical Model; Procedures; Property; Protein Engineering; Protein Fragment; Proteins; Rattus; Recombinant Antibody; Recombinants; Research; Sampling; Sodium; Sodium Channel; Structure; Technology; Therapeutic; Therapeutic antibodies; Validation; Vertebral column; base; chronic pain management; design; extracellular; flexibility; immunogenicity; in vivo; mimetics; nanobodies; novel; novel strategies; novel therapeutics; pain model; pain signal; pre-clinical; programs; protein folding; rational design; screening; structural biology; success; targeted treatment; therapeutic candidate; therapeutic development; trend; voltage

Our overarching goal is to develop conformationally-specific recombinant monoclonal antibodies (R-mAb) including Immunoglobulin G (IgG), single chain variable fragments (scFv) and nanobody (nAb) formats as a novel class of biologics to target voltage-gated sodium (Nav) channels involved in pain signaling. Recent breakthroughs in the structural biology of ion channels and Rosetta computational approaches for enhanced design and refinement of antigens, antibodies (Abs) and stable peptides have set the stage for applying rational design approaches to create conformationally-selective antibodies as superior therapeutic candidates to treat chronic pain. Advances recombinant Ab technology allows for the generation of a broader set of candidate therapeutics in different formats, yet with complementary attributes, that when used in conjunction further increases the likeliehood of success. To pursue the goals of this project we will assemble a diverse and interdisciplinary research team that will include experts in pain biology, development of therapeutics, development of Abs in R-mAb, scFv and nAb formats, computational protein design, neuroscience, electrophysiology, pharmacology, biostatistics, and preclinical models of pain. This project will establish our expert research team and generate preliminary data that would support rationale, feasibility, and validity of our rational design approach for a subsequent Team Research U19 grant application (RFA-NS-21-015). Human genetic studies have identified the Nav1.7, Nav1.8, and Nav1.9 channel subtypes as critical mediators of action potential generation in C-fiber nociceptors, and established these channels as molecular targets for pain therapy. There is a growing trend toward targeting ion channels with biologics, and we will use this approach to identify novel biological therapeutics for the treatment of pain. In particular, mAbs have emerged as prominent therapeutics due to their low immunogenicity, high selectivity, and favorable half-lives, and there are currently >130 different FDA approved mAbs in various formats in clinical use. Following initial studies with polyclonal Abs that demonstrated the technical feasibility, multiple preclinical programs are now using the full spectrum of available technologies to generate diverse forms of Abs against extracellular loops of ion channels. An immunogen design approach, using the Rosetta modelling software, has been recently developed to stabilize protein structural motifs as effective antigens to generate Abs targeting precisely defined epitopes. Our research team will be in a unique position to use our novel structure-based approach and apply our interdisciplinary expertise to develop conformationally-specific mAbs. We propose to design small proteins presenting epitope mimetics from human Nav1.7, Nav1.8, and Nav1.9 channels followed by generation and characterization of mAbs in IgG, scFv and nAb formats against the stabilized epitopes to develop therapeutic antibodies to treat chronic pain.

我们的总体目标是开发特定于构象的重组单克隆抗体（R-MAB） 包括免疫球蛋白G（IgG），单链变量片段（SCFV）和纳米型（NAB）格式作为A 新型的生物制剂靶向涉及疼痛信号传导的电压门控钠（NAV）通道。最近的 离子通道和罗塞塔计算方法的结构生物学的突破，以增强 抗原，抗体（ABS）和稳定肽的设计和改进已为应用理性奠定了阶段 设计方法来创建构象选择性抗体作为治疗的优质治疗候选者 慢性疼痛。进步重组AB技术允许产生更广泛的候选人 以不同格式的治疗剂，但具有互补属性，该属性是在连词中进一步使用的 增加了成功的可能性。为了实现该项目的目标，我们将组装多样的 跨学科研究团队将包括疼痛生物学专家，治疗学的发展， R-MAB，SCFV和NAB格式的ABS开发，计算蛋白设计，神经科学， 电生理学，药理学，生物统计学和临床​​前疼痛模型。这个项目将确定我们的 专家研究团队并生成初步数据，以支持我们的理由，可行性和有效性 随后的团队研究U19赠款应用程序（RFA-NS-21-015）的合理设计方法。人类 遗传研究已将NAV1.7，NAV1.8和NAV1.9通道亚型确定为关键作用介质 C纤维伤害感受器的潜在产生，并将这些通道确立为疼痛治疗的分子靶标。 用生物制剂靶向离子渠道的趋势越来越大，我们将使用这种方法来识别 用于治疗疼痛的新型生物学疗法。特别是，mab已经出现了 治疗药由于其免疫原性低，高选择性和有利的半衰期而引起的，目前有 > 130个不同的FDA以各种格式批准了临床用途的mAB。经过多克隆ABS的初步研究 这证明了技术可行性，现在正在使用多个临床前程序 可用的技术，以针对离子通道的细胞外回路产生各种形式的ABS。一个 使用Rosetta建模软件的免疫原设计方法最近已开发出来稳定 蛋白质结构基序作为有效抗原产生ABS靶向精确定义的表位的有效抗原。我们的研究 团队将处于使用我们新颖的基于结构的方法并运用我们的跨学科的独特位置 开发构象特异性单元单元的专业知识。我们建议设计表现出表位的小蛋白质 来自人类NAV1.7，NAV1.8和NAV1.9频道的Mimetics随后产生和表征 IgG，SCFV和NAB格式的mAb针对稳定表位以开发治疗抗体以治疗 慢性疼痛。