Preclinical Evaluation of Advanced Pan-Lassa Immunotherapeutic Cocktails
先进的泛拉沙免疫治疗混合物的临床前评估
基本信息
- 批准号:10617738
- 负责人:
- 金额:$ 165.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdultAfricaAfricanAnimal ModelAntibodiesAntibody FormationAntibody titer measurementArenavirusBindingBispecific AntibodiesCRISPR/Cas technologyCaviaCell LineCharacteristicsChemistryChinese Hamster Ovary CellClassificationClinicalClinical ResearchClinical TrialsComplementComplexConvalescenceDataDerivation procedureDiseaseDisease OutbreaksDoseDrug KineticsEconomicsEngineeringEpitopesEscape MutantEtiologyEvaluationGP2 geneGTPBP1 geneGenerationsGeographyGlycoproteinsHIV-1IgG1Immune systemImmunization ProgramsImmunotherapeutic agentIndividualInfectionInfection preventionInfectious AgentIntoxicationInvestigational DrugsInvestigational New Drug ApplicationLassa FeverLassa virusMalignant NeoplasmsModelingModificationNamesNational Institute of Allergy and Infectious DiseaseNigeriaPatientsPerformancePharmacology and ToxicologyPhasePolysaccharidesProductionPropertyReadinessRecommendationRecrudescencesReportingResolutionRodentStructureSymptomsTherapeuticToxic effectVaccinesViralViral AntigensViral Hemorrhagic FeversVirionVirusantibody engineeringantimicrobial drugdesignemerging pathogenexperiencefirst-in-humanhuman monoclonal antibodiesimprovedin vivoin vivo evaluationinfectious disease treatmentmachine learning algorithmmanufacturemonomerneutralizing monoclonal antibodiesnext generationnonhuman primatenovelopen labelpharmacologicpre-clinicalpreclinical evaluationprophylacticprotective efficacyrational designsocialsurveillance datatherapeutic candidatevolunteerweapons
项目摘要
Lassa fever (LF) is an often-fatal viral hemorrhagic fever (VHF) endemic in West Africa. A combination of three
broadly neutralizing human monoclonal antibodies (BNhMAbs) derived from West African patients who
survived LF (Arevirumab-3) rescued 100% of nonhuman primates (NHPs), even after delay in initiation of
treatment to 8 days post-infection. Recently, we solved the crystal structure of the pre-fusion form of the Lassa
virus glycoprotein complex (GPC) bound to a BNhMAb, the first structure for the virion configuration of the
GPC of any arenavirus. Additional newly solved structures for GPC:BNhMAb complexes and derivation of
escape mutants have informed the design and evaluation of optimally formulated BNhMAb cocktails targeting
independent neutralizing epitopes. We plan to expand upon this extensive body of work to support completion
of pre-clinical evaluation of Arevirumab-3 and functionally enhanced derivatives with improved
pharmacological properties toward first-in-human clinical studies with this novel class of LF therapeutics. In
studies proposed under Specific Aim 1, we will complete the pre-clinical evaluation of Arevirumab-3.
Completion of Chemistry, Manufacturing and Control Data (CMC), preclinical pharmacology and toxicology in
animal models of LF, including prophylactic interval and recrudescence evaluations, will enable the filing of an
Investigational New Drug (IND) application toward clinical studies with Arevirumab-3 The protective activity of
non-neutralizing LASV huMAbs in animal models of LF will be evaluated in studies proposed in Specific Aim
2. The protective efficacy of non-neutralizing LASV huMAbs will be evaluated and down-selected in guinea
pigs. If non-neutralizing protective huMAbs (NNPhuMAbs) are identified, the activity of this class of antibodies
will be further evaluated in NHP models of LF, either individually or in rationally designed cocktails. In studies
proposed under Specific Aim 3, we will design enhanced immunotherapeutics via Fc effector and
computational optimization, bi-specific antibody engineering (BsAbs), “designer” production cell lines that
attach specific glycans, and surveillance data inputs. Enhancement of immunotherapeutic cocktails with Fc
engineering, evaluation of BsAbs, machine learning algorithms, and CRISPR/Cas9-based generation of NS0
or CHO production cell lines with designer modifications will define characteristics of next generation LF
immunotherapeutics. Surveillance of circulating and emerging clinical LASV strains will educate the design of
LF immunotherapeutics with robust clinical characteristics and sustained potency. Under Specific Aim 4, we
propose studies to valuate in vivo protection and PK of optimized BNhMAbs, NNPhMAbs, and BsAbs. In vivo
evaluation of optimized LASV antibodies in established models of LF will educate advanced pre-clinical
evaluation of second generation immunotherapeutics with improved pharmacological properties. The studies
proposed in Project 1 are expected to result in the filing of an IND application for Arevirumab-3 in Year 3 and
a Pre-IND for a 2nd generation therapeutic at the conclusion of the 5-year performance period.
拉沙热是西非流行的一种常常致命的病毒性出血热。三者的组合
来自西非患者的广泛中和人类单抗(BNhMAbs)
存活的LF(Arevirumab-3)拯救了100%的非人类灵长类动物(HAP),即使在延迟启动
至感染后8天开始治疗。最近,我们解决了LASSA的预聚体形式的晶体结构
病毒糖蛋白复合体(GPC)与BNhMAb结合,是病毒粒子构型的第一个结构
任何病毒的GPC。GPC的其他新解结构:BNhMAb络合物及其衍生物
逃逸突变体为最佳配方BNhMAb靶向鸡尾酒的设计和评估提供了信息
独立中和表位。我们计划对这一广泛的工作进行扩展,以支持完成
对Arevirumab-3及其功能增强的衍生物进行临床前评估
这类新的LF治疗药物的药理学特性是人类临床研究中的第一例。在……里面
在特定目标1下提出的研究,我们将完成Arevirumab-3的临床前评估。
完成化学、制造和控制数据(CMC)、临床前药理学和毒理学
LF的动物模型,包括预防间隔和复发评估,将使提交
新药(IND)在Arevirumab-3临床研究中的应用
肝功能衰竭动物模型中的非中和性LASV huMAb将在特定目的的研究中进行评估
2.对非中和LASV huMAb在豚鼠体内的保护效果进行评价和筛选
猪。如果鉴定出非中和保护性HuMAbs(NNPhuMAbs),这类抗体的活性
将在LFNHP模型中进一步评估,无论是单独的还是在合理设计的鸡尾酒中。在研究中
在具体目标3下提出,我们将通过Fc效应器和
计算优化、双特异性抗体工程(BsAbs)、“设计者”生产细胞系
附加特定的糖链和监控数据输入。FC对免疫治疗鸡尾酒的强化作用
工程、BsAbs评估、机器学习算法以及基于CRISPR/Cas9的NS0生成
或者经过设计师修改的CHO生产单元线将定义下一代LF的特征
免疫疗法。对临床流行的和新出现的LASV毒株的监测将教育设计
具有强大的临床特征和持续效力的LF免疫疗法。在具体目标4下,我们
建议开展研究,评估优化的BNhMAbs、NNPhMAbs和BsAbs的体内保护和PK。活体内
在已建立的肝功能衰竭模型中评估优化的LASV抗体将培养高级临床前
药理特性改善的第二代免疫疗法的评价。这些研究
在项目1中提出的这些药物预计将导致在第3年提交Arevirumab-3的IND申请,以及
在5年的表演期结束时进行第二代治疗的预IND。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robert F Garry其他文献
Erratum to: Lassa hemorrhagic fever in a late term pregnancy from northern Sierra Leone with a positive maternal outcome: case report
- DOI:
10.1186/1743-422x-8-480 - 发表时间:
2011-10-25 - 期刊:
- 影响因子:3.800
- 作者:
Luis M Branco;Matt L Boisen;Kristian G Andersen;Jessica N Grove;Lina M Moses;Ivana J Muncy;Lee A Henderson;John S Schieffellin;James E Robinson;James J Bangura;Donald S Grant;Vanessa N Raabe;balu M Fonnie;Eleina M Zaitsev;Pardis C Sabeti;Robert F Garry - 通讯作者:
Robert F Garry
RETRACTED ARTICLE: Reduced expression of Jak-1 and Tyk-2 proteins leads to interferon resistance in Hepatitis C virus replicon
- DOI:
10.1186/1743-422x-4-89 - 发表时间:
2007-09-18 - 期刊:
- 影响因子:3.800
- 作者:
Sidhartha Hazari;Lizeth Taylor;Salima Haque;Robert F Garry;Sander Florman;Ronald Luftig;Frederic Regenstein;Srikanta Dash - 通讯作者:
Srikanta Dash
RETRACTED ARTICLE: Small interfering RNA targeted to stem-loop II of the 5' untranslated region effectively inhibits expression of six HCV genotypes
- DOI:
10.1186/1743-422x-3-100 - 发表时间:
2006-11-27 - 期刊:
- 影响因子:3.800
- 作者:
Ramesh Prabhu;Robert F Garry;Srikanta Dash - 通讯作者:
Srikanta Dash
Proteomics computational analyses suggest that the bornavirus glycoprotein is a class III viral fusion protein (γ penetrene)
- DOI:
10.1186/1743-422x-6-145 - 发表时间:
2009-09-18 - 期刊:
- 影响因子:3.800
- 作者:
Courtney E Garry;Robert F Garry - 通讯作者:
Robert F Garry
An invitation to recent graduates: publish your dissertation/thesis background section as a review in Virology Journal
- DOI:
10.1186/1743-422x-4-46 - 发表时间:
2007-06-02 - 期刊:
- 影响因子:3.800
- 作者:
Robert F Garry - 通讯作者:
Robert F Garry
Robert F Garry的其他文献
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{{ truncateString('Robert F Garry', 18)}}的其他基金
Preclinical Evaluation of Advanced Pan-Lassa Immunotherapeutic Cocktails
先进的泛拉沙免疫治疗混合物的临床前评估
- 批准号:
10158449 - 财政年份:2019
- 资助金额:
$ 165.87万 - 项目类别:
Preclinical Evaluation of Advanced Pan-Lassa Immunotherapeutic Cocktails
先进的泛拉沙免疫治疗混合物的临床前评估
- 批准号:
10402339 - 财政年份:2019
- 资助金额:
$ 165.87万 - 项目类别:
Systems-level identification of host determinants of patient outcomes in Lassa fever and Ebola
拉沙热和埃博拉患者预后的宿主决定因素的系统级识别
- 批准号:
10374719 - 财政年份:2018
- 资助金额:
$ 165.87万 - 项目类别:
Systems-level identification of host determinants of patient outcomes in Lassa fever and Ebola
拉沙热和埃博拉患者预后的宿主决定因素的系统级识别
- 批准号:
10310605 - 财政年份:2018
- 资助金额:
$ 165.87万 - 项目类别:
Systems-level identification of host determinants of patient outcomes in Lassa fever and Ebola
拉沙热和埃博拉患者预后的宿主决定因素的系统级识别
- 批准号:
10579086 - 财政年份:2018
- 资助金额:
$ 165.87万 - 项目类别:
Structure-based design of novel Lassa virus glycoproteins for vaccine development
用于疫苗开发的新型拉沙病毒糖蛋白的基于结构的设计
- 批准号:
10202410 - 财政年份:2017
- 资助金额:
$ 165.87万 - 项目类别:
Preclinical evaluation of a potent Lassa fever immunotherapeutic antibody cocktail
有效的拉沙热免疫治疗抗体混合物的临床前评估
- 批准号:
9926211 - 财政年份:2017
- 资助金额:
$ 165.87万 - 项目类别:
Preclinical evaluation of a potent Lassa fever immunotherapeutic antibody cocktail
有效的拉沙热免疫治疗抗体混合物的临床前评估
- 批准号:
10176382 - 财政年份:2017
- 资助金额:
$ 165.87万 - 项目类别:
Structure-based design of novel Lassa virus glycoproteins for vaccine development
用于疫苗开发的新型拉沙病毒糖蛋白的基于结构的设计
- 批准号:
10438220 - 财政年份:2017
- 资助金额:
$ 165.87万 - 项目类别:
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