Glycoengineering eCD4-Ig
糖工程 eCD4-Ig
基本信息
- 批准号:10589151
- 负责人:
- 金额:$ 100万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-09 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AntibodiesAreaAsialoglycoprotein ReceptorBindingCarbohydratesCell LineChinese Hamster Ovary CellCirculationCyclic GMPDNA cassetteDataDoseDrug KineticsEngineeringEnzymesFCGR3B geneFucoseGalactoseGlucosamineGlycoengineeringGoalsHIVHIV InfectionsHIV ReceptorsHalf-LifeHumanInfectionInjectableLinkLongevityMacaca mulattaMannoseMediatingMuscleNational Institute of Allergy and Infectious DiseasePharmaceutical PreparationsPlasmaPolysaccharidesPrimatesPropertyProteinsRecombinant ProteinsSIVSialic AcidsTestingTherapeuticTherapeutic antibodiesTimeTransgenic MiceTreatment EfficacyViral Load resultWorkadeno-associated viral vectorantibody mimeticsantibody-dependent cell cytotoxicitycarbohydrate structuredimerglycosylationhead-to-head comparisonimprovedinhibiting antibodyknock-downmanufacturemouse modelneonatal Fc receptorneutralizing antibodyoverexpressionpeptidomimeticspreventreceptorreceptor bindingsialylationsmall hairpin RNAstable cell linesugartherapeutic proteinviral resistance
项目摘要
ABSTRACT
We are developing eCD4-Ig, an antibody-like molecule constructed from CD4, a coreceptor-mimetic
peptide, and an antibody Fc, as a long-acting injectable therapeutic for HIV. Our progress to-date
includes having extended the plasma half-life of eCD4-Ig to the point that it now rivals or surpasses that
of the leading broadly neutralizing antibodies (bNAbs) being developed as long-acting injectables. In a
head-to-head comparison of pharmacokinetics (PK) in the human FcRn-transgenic mouse model,
eCD4-Ig had significantly better PK than a VRC01 protein that had a half-life of 71 days in humans
(Gaudinski et al., PLoS Med, 2018). With support from NIAID, we have developed a CHO cell line for
manufacturing eCD4-Ig under cGMP conditions. However, in-depth analysis of the composition of the
N-linked glycans (NLGs) at N297 of the Fc of the protein made by the cell line has highlighted a
problem shared by the entire field: The large majority of the NLGs are forms detrimental to PK. This
problem is particularly pronounced among the afucosylated forms that are active for antibody-
dependent cell-mediated cytotoxicity (ADCC). Indeed, only a few percent of the NLGs are afucosylated
forms that allow both ADCC and a long half-life. Therefore, we propose glycoengineering our cell line
for manufacturing eCD4-Ig. To do so, we will develop a glycoengineering gene cassette, introduce it
into the cell line, and derive a glycoengineered clone for manufacturing eCD4-Ig under cGMP
conditions. Although our primary goal is to manufacture eCD4-Ig protein consisting almost entirely of a
single long-lived glycoform that is active for ADCC, the same glycoengineering gene cassette can be
used to manufacture other antibody therapeutics, including bNAbs, to similarly extend effector function
and plasma half-life. This work will reduce the therapeutic concentration and increase the interval at
which long-acting protein therapeutics for treating and preventing HIV infection can be dosed.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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MICHAEL DAVID ALPERT其他文献
MICHAEL DAVID ALPERT的其他文献
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{{ truncateString('MICHAEL DAVID ALPERT', 18)}}的其他基金
SARS-CoV-2 vaccines based on RBDs with engineered glycosylation sites
基于带有工程化糖基化位点的 RBD 的 SARS-CoV-2 疫苗
- 批准号:
10867558 - 财政年份:2023
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Engineering AAV capsids for enhanced transduction of skeletal muscle
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10080465 - 财政年份:2020
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Engineering AAV capsids for enhanced transduction of skeletal muscle
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10394340 - 财政年份:2020
- 资助金额:
$ 100万 - 项目类别:
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