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
基本信息
- 批准号:10252440
- 负责人:
- 金额:$ 71.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:2019-nCoVAdenovirusesAnimalsAntibodiesAntigensAreaAutologousBacteriaBindingBloodBlood TestsBlood TransfusionBlood donorBlood-Borne PathogensCOVID-19COVID-19 patientCOVID-19 treatmentChimeric ProteinsCollaborationsCommunicable DiseasesCritical IllnessDetergentsDevelopmentDiseaseEmerging Communicable DiseasesEnzyme-Linked Immunosorbent AssayErythrocyte TransfusionEvaluationExcisionFiltrationFundingFutureGoalsGrantGrowth FactorHematological DiseaseHospitalsHumanImmuneIndividualInfectionInfusion proceduresLicensingLifeMarketingModelingMycoplasmaNew YorkNucleic AcidsOryctolagus cuniculusPacked Red Blood Cell TransfusionPatientsPersonsPharmacologic SubstancePhasePlasmaPlasma ProteinsPolyaminesPreparationProceduresProcessPropertyProteinsProtozoaRNARecoveryReportingResearchResidual stateRiskSARS-CoV-2 antibodySARS-CoV-2 spike proteinSARS-CoV-2 transmissionSafetySalesSavingsSmall Business Innovation Research GrantSolventsTechnologyTestingTherapeuticTimeToxic effectTransfusionUnited States National Institutes of HealthVesicular stomatitis Indiana virusVirusVirus DiseasesVirus Inactivationanalytical methodbaseblood productconvalescent plasmadetection limiteffective therapyemerging pathogenexperiencefungusgamma irradiationhigh riskhuman coronavirusin vivonanoneutralizing antibodypasteurizationpathogenpathogen genomicspreclinical evaluationpreservationprophylacticresearch clinical testingscaffoldsuccessultraviolet irradiation
项目摘要
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
此外,还可以使用血浆或中和抗体进行治疗。
恢复期患者的制剂可能是新发传染病的唯一治疗方法
没有其他治疗方法可用。同时,CP 输血使接受者面临风险。
输血传播疾病 (TTD) 的风险因受损而进一步加剧
目前有限的TTD血液检测无法提供重症患者的免疫状况。
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获得病原体。
不幸的是,灭活可以提供解决方案,目前用于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。
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,我们灭活了不同类型的活性。
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
目前我们正在开发 ZPI,用于减少输血红细胞中的病原体,
由 NIH SBIR 拨款 (R44 HL145783) 资助的研究 在本申请中,我们建议采用新的方法。
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)
已经开发出分析方法来建立完全中和和/或去除的条件
处理后血浆中残留的灭活剂;(3)使用针对 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
(4) 使用针对 SARS-CoV-2 S 蛋白的中和抗体来证明
(5)使用重复的自体抗体进行血浆处理后的病毒中和特性;
输注经处理的血浆以建立其在兔体内模型中的安全性。
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,将授权治疗程序以完成其开发和营销。
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。
项目成果
期刊论文数量(0)
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David R Tabatadze其他文献
David R Tabatadze的其他文献
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{{ truncateString('David R Tabatadze', 18)}}的其他基金
A CLOSED SYSTEM FOR PATHOGEN REDUCTION OF RED BLOOD CELLS FOR TRANSFUSION
用于减少输血红细胞病原体的封闭系统
- 批准号:
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- 资助金额:
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SELF-NEUTRALIZING OLIGONUCLEOTIDES WITH ENHANCED CELLULAR UPTAKE
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8775829 - 财政年份:2014
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SELF-NEUTRALIZING OLIGONUCLEOTIDES WITH ENHANCED CELLULAR UPTAKE
增强细胞吸收的自中和寡核苷酸
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9281767 - 财政年份:2014
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