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: 10611494
• 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/10611494
• 关键词: Acceleration; Achievement; Antibodies; Antibody Binding Sites; Antibody-Dependent Enhancement; Binding; Cancer Model; Development; Disease; Drug Kinetics; Drug Targeting; Engineering; Enzyme Inhibition; Epitopes; Family; Generations; Half-Life; Health; Human; Hybridomas; Laboratories; Malignant Neoplasms; Membrane; Methodology; Methods; Monoclonal Antibodies; Obesity; Pathogenesis; Pathology; Peptide Hydrolases; Pharmacologic Substance; Physiological Processes; Prodrugs; Property; Protease Inhibitor; Public Health; Research; SARS-CoV-2 inhibitor; 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; blood-brain barrier crossing; drug discovery; high throughput screening; inhibiting antibody; inhibitor therapy; invention; mouse model; new technology; painful neuropathy; programs; 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.

项目概要 作为重要的信号分子，蛋白酶精确地控制着多种生理过程。 健康和疾病，因此代表最大的药物靶标家族之一。尽管几十年 经过大量努力，传统的药物发现策略仅通过靶向药物取得了有限的成功。 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 有效且安全的基于蛋白酶的治疗所需的特异性和/或适当的药代动力学特性。 在这些方面，单克隆抗体 (mAb) 正在成为有吸引力的替代品，具有显着的优势 具有选择性高、血清半衰期长、穿过血脑屏障的潜力等优点 诱导型前药。自杂交瘤技术发明以来，单克隆抗体研究取得了巨大进展 发现和工程。然而，蛋白酶抑制单克隆抗体的常规发现仍然是一个相当大的任务。 一般来说，由于人抗体互补位对酶抑制的不相容性，以及缺乏 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，促进作为安全有效的蛋白酶产生治疗性单克隆抗体 抑制剂。五年来，我们取得了长足的进步，建立了一系列新颖的 技术，包括受骆驼启发的凸互补位人类抗体库，以及基于抑制的而非 比基于结合的选择/筛选方法。结合这些可行的方法，我们发现， 经过表征和优化的有效和特异性单克隆抗体组，可抑制多种生物医学蛋白酶 重要性。此外，我们的蛋白酶抑制单克隆抗体在小鼠中显示出显着的治疗效果 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，这些 成就开启了令人兴奋的机遇。未来五年，我们将拓展我们的实力 许多其他有据可查的蛋白酶的技术，其中迫切需要治疗性抑制剂。 此外，我们将开发额外的技术来实现独特且治疗所需的功能：(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，以及 (3) 通过合理设计进行表位特异性抑制。总体而言，据估计蛋白酶占 5-10% 的所有药物靶点均已进行药物开发研究。拟议研究的完成将 明确推进针对生物医学重要蛋白酶的治疗性单克隆抗体开发，例如反对 通过抑制 TMPRSS2（II 型跨膜丝氨酸蛋白酶）来应对当前的危险 SARS-CoV-2 中和方法，没有不需要的抗体依赖性增强。

项目成果

Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor.

• DOI: 10.1038/s41467-022-31563-2
• 发表时间: 2022-06-29
• 期刊: Nature communications
• 影响因子: 16.6

Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2.

• DOI: 10.1038/s41467-022-35590-x
• 发表时间: 2022-12-23
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Guo, Xuanming;Cao, Jianli;Cai, Jian-Piao;Wu, Jiayan;Huang, Jiangang;Asthana, Pallavi;Wong, Sheung Kin Ken;Ye, Zi-Wei;Gurung, Susma;Zhang, Yijing;Wang, Sheng;Wang, Zening;Ge, Xin;Kwan, Hiu Yee;Lyu, Aiping;Chan, Kui Ming;Wong, Nathalie;Huang, Jiandong;Zhou, Zhongjun;Bian, Zhao-Xiang;Yuan, Shuofeng;Wong, Hoi Leong Xavier
• 通讯作者: Wong, Hoi Leong Xavier

High-fidelity large-diversity monoclonal mammalian cell libraries by cell cycle arrested recombinase-mediated cassette exchange.

• DOI: 10.1093/nar/gkad1001
• 发表时间: 2023-12-11
• 期刊: Nucleic acids research
• 影响因子: 14.9

Monitoring In Vivo Performances of Protein-Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging.

• DOI: 10.1021/acs.jmedchem.2c00401
• 发表时间: 2022-05-12
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Cahuzac, Heloise;Sallustrau, Antoine;Malgorn, Carole;Beau, Fabrice;Barbe, Peggy;Babin, Victor;Dubois, Steven;Palazzolo, Alberto;Thai, Robert;Correia, Isabelle;Lee, Ki Baek;Garcia-Argote, Sebastien;Lequin, Olivier;Keck, Mathilde;Nozach, Herve;Feuillastre, Sophie;Ge, Xin;Pieters, Gregory;Audisio, Davide;Devel, Laurent
• 通讯作者: Devel, Laurent

Generation of Protease Inhibitory Antibodies by Functional In Vivo Selection.

通过功能性体内选择产生蛋白酶抑制抗体。

• DOI: 10.1007/978-1-0716-3589-6_19
• 发表时间: 2024
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Lee,KiBaek;Ge,Xin
• 通讯作者: Ge,Xin