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

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(LF)是西非一种通常致命的病毒性出血热(VHF)。三个的组合

项目成果

期刊论文数量(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:
Project 1
项目1
  • 批准号:
    10558423
  • 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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