Highly Selective Pathogen Inactivators For Treatment of Convalescent Transfusion Plasma

用于治疗恢复期输血血浆的高选择性病原体灭活剂

• 批准号: 10252440
• 负责人: David R Tabatadze
• 金额: $ 71.76万
• 依托单位: ZATA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 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/10252440
• 关键词: 2019-nCoV; Adenoviruses; Animals; Antibodies; Antigens; Area; Autologous; Bacteria; Binding; Blood; Blood Tests; Blood Transfusion; Blood donor; Blood-Borne Pathogens; COVID-19; COVID-19 patient; COVID-19 treatment; Chimeric Proteins; Collaborations; Communicable Diseases; Critical Illness; Detergents; Development; Disease; Emerging Communicable Diseases; Enzyme-Linked Immunosorbent Assay; Erythrocyte Transfusion; Evaluation; Excision; Filtration; Funding; Future; Goals; Grant; Growth Factor; Hematological Disease; Hospitals; Human; Immune; Individual; Infection; Infusion procedures; Licensing; Life; Marketing; Modeling; Mycoplasma; New York; Nucleic Acids; Oryctolagus cuniculus; Packed Red Blood Cell Transfusion; Patients; Persons; Pharmacologic Substance; Phase; Plasma; Plasma Proteins; Polyamines; Preparation; Procedures; Process; Property; Proteins; Protozoa; RNA; Recovery; Reporting; Research; Residual state; Risk; SARS-CoV-2 antibody; SARS-CoV-2 spike protein; SARS-CoV-2 transmission; Safety; Sales; Savings; Small Business Innovation Research Grant; Solvents; Technology; Testing; Therapeutic; Time; Toxic effect; Transfusion; United States National Institutes of Health; Vesicular stomatitis Indiana virus; Virus; Virus Diseases; Virus Inactivation; analytical method; base; blood product; convalescent plasma; detection limit; effective therapy; emerging pathogen; experience; fungus; gamma irradiation; high risk; human coronavirus; in vivo; nano; neutralizing antibody; pasteurization; pathogen; pathogen genomics; preclinical evaluation; preservation; prophylactic; research clinical testing; scaffold; success; ultraviolet irradiation

ABSTRACT Presently, convalescent plasma (CP) transfusion is being developed as a therapy for COVID-19 patients and as a prophylactic for high risk individuals. In addition, treatment with plasma or neutralizing antibody preparations from convalescent patients could be the only treatment for emerging infectious diseases, for which no other treatments may be available. At the same time, CP transfusion exposes the recipient to the risk of transfusion transmitted diseases (TTD), a risk which is additionally exacerbated by the compromised immune conditions of the critically ill patients. The limited number of current TTD blood tests does not provide for full protection, restrict the critically limited donor’s pool and may not be available in some areas. Pathogen Inactivation can provide the solution. Unfortunately, the currently utilized treatments for pathogen reduction in plasma (solvent-detergent, pasteurization of dry heat, UV or gamma irradiations) are non-selective and can compromise the quality of plasma’s neutralizing antibodies or other protective protein factors. We at ZATA Pharmaceuticals have developed a new class of pathogen inactivators (ZPI) based on the natural polyamines scaffold, which are truly selective in inactivating pathogens genomic molecules while sparing plasma proteins. Our preliminary results show that ZPI have high reactivity toward nucleic acids and do not modify model proteins (Cyt-C, RSV fusion protein) and animal sera growth factors. Using them, we inactivated different types of pathogens (G+ and G- bacteria, mycoplasma, fungi, protozoa) and high titer preparations of enveloped or non-enveloped viruses. Currently we are developing ZPI for pathogens reduction in transfusion red blood cells, research funded by NIH SBIR grant (R44 HL145783). In this application we propose to adapt the new pathogen inactivation process for treatment of convalescent plasma (CP) by: (1) using 6 virus species in human plasma to select the optimal ZPI and conditions for pathogen inactivation in human plasma; (2) using already developed analytical methods to establish conditions for complete neutralization and/or removal of the residual inactivator from the treated plasma; (3) using specific antibodies against 4 virus species to demonstrate by ELISA that the virus inactivation treatment has no effect on the binding of the antibodies to their targets; (4) using neutralizing antibodies against SARS-CoV-2 S protein to demonstrate preservation of the virus neutralizing properties of the antibodies after plasma treatment; (5) using repeated autologous infusion of treated plasma to establish its in vivo the safety in the rabbit models. After accomplishment of those initial goals we will apply for funding, including SBIR funding to complete, in collaboration with New York Blood Center, its pre-clinical evaluation and to initiate phase I human trials, or alternatively, will license the treatment procedure for completion of its development and marketing. Ultimately, this proposal will lead to a safe and high quality convalescent human plasma for treatment or prophylactics of COVID19 or other deadly diseases for which no other effective treatment is currently available.

抽象的 目前，正在为Covid-19患者开发疗养血浆（CP）输血作为一种疗法 作为高风险个体的预防性。此外，用血浆或中和抗体处理 康复患者的准备可能是新兴传染病的唯一治疗方法 可能没有其他治疗。同时，CP输血将接收者暴露于风险 输血传播疾病（TTD） 重症患者的免疫状况。当前的TTD血液测试数量有限 为了进行全面保护，请限制非常有限的捐助者游泳池，并且可能在某些地区不可用。病原 灭活可以提供解决方案。不幸的是，目前利用的治疗方法用于降低病原体 血浆（溶剂少，干热的巴氏灭菌，紫外线或伽马射线）是非选择性的，可以 损害血浆中和抗体或其他保护蛋白因子的质量。我们在Zata 药物已经基于天然多胺开发了一类新的病原体灭活剂（ZPI） 脚手架，在损害病原体基因组分子时真正有选择性，同时保留血浆蛋白。 我们的初步结果表明，ZPI对核酸具有很高的反应性，并且不修改模型 蛋白质（CYT-C，RSV融合蛋白）和动物血清生长因子。使用它们，我们灭活了不同的类型 病原体（G+和G-细菌，支原体，真菌，原生动物）和高滴水的材料制剂 非发育的病毒。目前，我们正在开发ZPI，以减少输血红细胞的病原体， 由NIH SBIR Grant（R44 HL145783）资助的研究。在此应用程序中，我们建议适应新的 病原体灭活过程，用于治疗康复血浆（CP）的病原体：（1）使用6种病毒物种 人血浆选择人血浆中的最佳ZPI和病原体失活的条件； （2）使用 已经开发了分析方法，以建立完全中和和/或去除的条件 从处理的血浆中的残留灭活剂； （3）使用针对4种病毒规格的特定抗体 ELISA证明病毒灭活治疗对抗体与 他们的目标； （4）使用针对SARS-COV-2 S蛋白的中和抗体证明保存 血浆治疗后的抗体的病毒中和特性； （5）使用重复的自体 输注经过处理的血浆以在兔模型中建立其在体内的安全性。 实现了这些最初目标后，我们将申请资金，包括SBIR资金完成， 与纽约血液中心合作，临床前评估并启动I期人类试验或 另外，将许可完成其开发和营销的治疗程序。最终， 该建议将导致安全，高质量的康复人血浆治疗或预防药物的治疗方法 Covid19或其他目前没有其他有效治疗的致命疾病。