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，正在开发恢复期血浆（CP）输注作为 COVID-19 患者的治疗方法 并作为高危人群的预防措施。此外，用血浆或中和抗体治疗 恢复期患者的制剂可能是新发传染病的唯一治疗方法 可能没有其他治疗方法可用。同时，CP输血使受血者面临风险 输血传播疾病 (TTD) 的风险因受损而进一步加剧 重症患者的免疫状况。目前 TTD 血液检测数量有限，无法提供 为了获得充分的保护，请限制极其有限的捐赠者池，并且在某些地区可能无法使用。病原 灭活可以提供解决方案。不幸的是，目前使用的减少病原体的治疗方法 等离子体（溶剂清洁剂、干热巴氏灭菌、紫外线或伽马射线照射）是非选择性的，可以 损害血浆中和抗体或其他保护性蛋白质因子的质量。我们在扎塔 制药公司开发了一种基于天然多胺的新型病原体灭活剂 (ZPI) 支架，真正选择性地灭活病原体基因组分子，同时保留血浆蛋白。 我们的初步结果表明ZPI对核酸具有高反应性并且不修改模型 蛋白（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）和包膜或高滴度制剂 无包膜病毒。目前我们正在开发ZPI，用于减少输血红细胞中的病原体， 研究由 NIH SBIR 拨款 (R44 HL145783) 资助。在此应用中，我们建议采用新的 用于处理恢复期血浆 (CP) 的病原体灭活过程如下： (1) 使用 6 种病毒 人血浆，以选择人血浆中病原体灭活的最佳 ZPI 和条件； (2)使用 已经开发出分析方法来建立完全中和和/或去除的条件 处理过的血浆中残留的灭活剂； (3)利用针对4种病毒的特异性抗体 通过ELISA证明病毒灭活处理对抗体的结合没有影响 他们的目标； (4) 使用针对 SARS-CoV-2 S 蛋白的中和抗体来证明 血浆处理后抗体的病毒中和特性； (5)使用重复自体 输注处理过的血浆以建立其在兔模型中的体内安全性。 完成这些初步目标后，我们将申请资金，包括 SBIR 资金以完成 与纽约血液中心合作，进行临床前评估并启动第一阶段人体试验，或 或者，将许可治疗程序以完成其开发和营销。最终， 该提案将产生安全、高质量的恢复期人血浆，用于治疗或预防 新冠肺炎 (COVID19) 或其他目前尚无其他有效治疗方法的致命疾病。