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.

我们的首要目标是开发构象特异性重组单克隆抗体 (R-mAb) 包括免疫球蛋白 G (IgG)、单链可变片段 (scFv) 和纳米抗体 (nAb) 格式 新型生物制剂，针对参与疼痛信号传导的电压门控钠 (Nav) 通道。最近的 离子通道结构生物学的突破和 Rosetta 计算方法增强 抗原、抗体 (Ab) 和稳定肽的设计和完善为合理应用奠定了基础 设计方法来创建构象选择性抗体作为治疗的优质候选药物 慢性疼痛。先进的重组抗体技术可以产生更广泛的候选抗体 不同形式的疗法，但具有互补的属性，当结合使用时，可以进一步 增加成功的可能性。为了实现该项目的目标，我们将组建多元化和 跨学科研究团队将包括疼痛生物学、治疗学开发、 R-mAb、scFv 和 nAb 格式的抗体开发、计算蛋白质设计、神经科学、 电生理学、药理学、生物统计学和疼痛的临床前模型。该项目将建立我们的 专家研究团队并生成初步数据，以支持我们的基本原理、可行性和有效性 后续 Team Research U19 拨款申请 (RFA-NS-21-015) 的合理设计方法。人类 遗传学研究已确定 Nav1.7、Nav1.8 和 Nav1.9 通道亚型是作用的关键介质 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点。 用生物制剂靶向离子通道的趋势日益增长，我们将使用这种方法来识别 用于治疗疼痛的新型生物疗法。特别是，单克隆抗体已成为突出的 因其低免疫原性、高选择性和良好的半衰期而成为治疗药物，目前有 > 130 种 FDA 批准的不同形式的单克隆抗体可用于临床使用。多克隆抗体初步研究之后 证明了技术可行性，多个临床前项目现在正在使用全谱 现有技术可产生针对离子通道细胞外环的多种形式的抗体。一个 最近开发了使用 Rosetta 建模软件的免疫原设计方法来稳定 蛋白质结构基序作为有效抗原，产生针对精确定义的表位的抗体。我们的研究 团队将处于独特的地位，可以使用我们新颖的基于结构的方法并应用我们的跨学科 开发构象特异性单克隆抗体的专业知识。我们建议设计呈递表位的小蛋白质 来自人类 Nav1.7、Nav1.8 和 Nav1.9 通道的模拟物，然后生成和表征 针对稳定表位的 IgG、scFv 和 nAb 形式的 mAb，可开发治疗性抗体来治疗 慢性疼痛。