Therapeutic Monoclonal Antibodies Inhibiting Proteases of Biomedical Importance

抑制具有生物医学重要性的蛋白酶的治疗性单克隆抗体

• 批准号: 10434848
• 负责人: Xin Ge
• 金额: $ 39万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434848
• 关键词: 2019-nCoV; Achievement; Antibodies; Antibody Binding Sites; Antibody-Dependent Enhancement; Binding; Blood - brain barrier anatomy; Cancer Model; Development; Disease; Drug Kinetics; Drug Targeting; Engineering; Enzyme Inhibition; Epitopes; Family; Generations; Half-Life; Health; Human; Hybridomas; Laboratories; Lead; Malignant Neoplasms; Methodology; Methods; Monoclonal Antibodies; Obesity; Pathogenesis; Pathology; Peptide Hydrolases; Pharmacologic Substance; Physiological Processes; Prodrugs; Property; Protease Inhibitor; Public Health; Research; Series; Serine Protease; Serum; Signaling Molecule; Specificity; Stroke; TMPRSS2 gene; Technology; Therapeutic; Therapeutic Intervention; Therapeutic Monoclonal Antibodies; Treatment Efficacy; Virus Diseases; antibody inhibitor; antibody libraries; base; drug discovery; high throughput screening; inhibiting antibody; inhibitor therapy; invention; mouse model; new technology; painful neuropathy; programs; protease E; rational design; screening; small molecule inhibitor; success; therapeutic development

PROJECT SUMMARY As important signaling molecules, proteases precisely control a wide variety of physiological processes both in health and in diseases, and thus represent one of the largest families of pharmaceutical targets. Despite decades of intensive efforts, conventional drug discovery strategies have only achieved a limited success by targeting a small fraction of all therapeutically relevant proteases. It is because small-molecule inhibitors are often lack of specificity and/or appropriate pharmacokinetic properties required for effective and safe protease-based therapy. In these aspects, monoclonal antibodies (mAbs) are emerging as attractive alternatives with significant advantages such as high selectivity, long serum half-life, potential to cross the blood-brain barrier, and as inducible prodrugs. Since the invention of hybridoma technology, tremendous progress has been made in mAb discovery and engineering. However, routine discovery of protease-inhibiting mAbs is still a considerable challenge in general, due to the incompatibility of human antibody paratope for enzyme inhibition, and lack of functional high-throughput screening methods. My laboratory has been committed to the development of streamlined methodologies that facilitate the generation of therapeutic mAbs as safe and effective protease inhibitors. Over the past five years, we have made significant progress, and established a series of novel technologies, including camelid-inspired convex paratope human antibody libraries, and inhibition-based rather than binding-based selection/screening methods. Combining these enabling approaches, we discovered, characterized, and optimized panels of potent and specific mAbs inhibiting numerous proteases of biomedical importance. Furthermore, our protease inhibitory mAbs have shown significant therapeutic efficacy in mouse models of cancers, neuropathic pains, obesity, and stroke. By overcoming longstanding challenges, these achievements have opened the exciting opportunity. In the next five years, we will extend our powerful technologies to many other well-documented proteases, of which therapeutic inhibitors are urgently needed. Furthermore, we will develop additional technologies to achieve unique and therapy-desirable features: (1) function-specific (substrate-dependent) inhibition, (2) broad-spectrum inhibition on a group of proteases, and (3) epitope-specific inhibition by rational design. Overall, it has been estimated that proteases account for 5-10% of all drug targets have been studied for pharmaceutical development. The completion of proposed research will unambiguously advance therapeutic mAb developments targeting biomedically important proteases, e.g. against the present danger, SARS-CoV-2, by inhibiting TMPRSS2 (type II transmembrane serine protease) as a broad neutralization approach without the unwanted antibody-dependent enhancement.

项目摘要 蛋白酶作为重要的信号分子，精确地控制着多种生理过程， 在健康和疾病中，因此代表了最大的药物靶标家族之一。尽管几十年 尽管进行了大量的努力，但传统的药物发现策略只取得了有限的成功， 所有治疗相关蛋白酶的一小部分。这是因为小分子抑制剂往往缺乏 特异性和/或有效和安全的基于蛋白酶的治疗所需的适当的药代动力学性质。 在这些方面，单克隆抗体（mAb）正在成为具有显著生物学活性的有吸引力的替代物。 优点如高选择性、长血清半衰期、穿过血脑屏障的潜力，以及 诱导型前药自杂交瘤技术发明以来，单克隆抗体的研究取得了巨大的进展 发现和工程。然而，常规发现蛋白酶抑制单克隆抗体仍然是一个相当大的挑战。 一般来说，由于人抗体互补位对酶抑制的不相容性， 功能性高通量筛选方法。我的实验室一直致力于开发 简化的方法，促进治疗性mAb的产生，作为安全有效的蛋白酶 抑制剂的在过去的五年里，我们取得了重大进展，并建立了一系列新颖的 技术，包括骆驼启发的凸互补位人类抗体库，和基于抑制的， 基于结合的选择/筛选方法。结合这些使能方法，我们发现， 表征和优化的有效和特异性mAb组，其抑制生物医学的多种蛋白酶， 重要性此外，我们的蛋白酶抑制性mAb在小鼠中显示出显著的治疗功效。 癌症、神经性疼痛、肥胖和中风的模型。通过克服长期存在的挑战， 成就开启了激动人心的机遇。在未来五年，我们将扩大我们强大的 这些技术应用于许多其他有据可查的蛋白酶，其中迫切需要治疗性抑制剂。 此外，我们将开发其他技术，以实现独特的和治疗所需的功能：（1） 功能特异性（底物依赖性）抑制，（2）对一组蛋白酶的广谱抑制，和（3） 通过合理设计实现表位特异性抑制。总的来说，据估计，蛋白酶占5-10% 所有药物靶点的研究已经用于药物开发。完成拟议的研究将 明确推进靶向生物医学重要蛋白酶的治疗性mAb开发，例如针对 目前的危险，SARS-CoV-2，通过抑制TMPRSS 2（II型跨膜丝氨酸蛋白酶）作为广泛的 中和方法，而没有不需要的抗体依赖性增强。