Administrative Supplement: Activity-based Discovery and Optimization
行政补充:基于活动的发现和优化
基本信息
- 批准号:10578077
- 负责人:
- 金额:$ 0.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2022-04-15
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAddressAdministrative SupplementAffectAffinityAgonistAntibodiesAutoimmune DiseasesBiologicalBiological AssayBiological ModelsBiological ProcessBiomedical TechnologyBiotechnologyCell SeparationCell physiologyCell surfaceCellsClinical TrialsComputer ModelsDetectionDevelopmentDiseaseEnzymesEvaluationEventFeedbackFoundationsFrequenciesGenetic EngineeringGoalsGoldHealthHumanHuman PathologyImmunoglobulin FragmentsIn VitroKnowledgeLeadLengthLibrariesLigandsLinkMalignant NeoplasmsMethodsMolecularOX40PathologicPathologyPathway interactionsReporterResearchSignal TransductionSorting - Cell MovementStructure-Activity RelationshipSurfaceSystemT-Cell ActivationT-Cell ReceptorT-LymphocyteTechnologyTherapeuticTherapeutic antibodiesTimeValidationVariantadvanced diseaseantagonistantibody engineeringbasebeta-Lactamasebiophysical propertiesbody systemdesigneffective therapyextracellularimprovedimproved functioningin silicoin vitro Assayinnovationinnovative technologieslead candidatenext generation sequencingnovelnovel therapeuticsreceptorreceptor-mediated signalingscreeningtherapeutic candidatetranscription factortumor necrosis factor receptor superfamily member 4wound healing
项目摘要
PROJECT SUMMARY
Agonist antibodies, capable of initiating cellular signaling events through interaction at the cell surface, have
emerged as a new paradigm in disease treatment with several promising candidates in clinical trials including T
cell activating antibodies. However, the discovery of rare antibodies possessing specific biological functions
remains a major biotechnological bottleneck. To address this issue, I seek to employ direct function-based
antibody screening methods, an emergent biomedical technology using mammalian intracellular reporter
systems for which proof-of-concept has recently been shown for the discovery of agonist antibodies. I believe
that this innovative technology has the potential to be revolutionary if it can be generalized. Thus, the goal of
the proposed research is to establish new fundamental methods for broad use in function-based antibody
screening, which could ultimately lay the foundation for advancing disease treatment. I have recently
developed novel model systems that enable robust detection of intracellular signaling via the NF-κB pathway
initiated from extracellular activation of the T-cell receptors Ox40 and CD137. These receptors were chosen for
their availability of well-defined control agonist antibodies that are invaluable for system validation. I propose to
use these model systems to gain new understanding of the fundamental mechanisms and principles involved
in function-based antibody screening and employ this knowledge toward the development of new biomedical
technology and novel therapeutics via three distinct aims. First, I propose to critically evaluate the relationship
between biological activity, antibody display level, receptor display level, and antibody molecular format to
identify screening methods that ultimately improve the efficiency of agonist antibody discovery. Second, I
propose to develop new Ox40 and CD137 reporter cell systems for simplified and improved function-based
antibody discovery via genetic engineering of autocatalytic agonist antibody expression that depends on
receptor-specific intracellular signaling in order to improve agonist antibody discovery by both simplifying signal
detection and amplifying true positive signals. Thirdly, I seek to identify new Ox40 and CD137 agonist
antibodies with improved activity by direct function-based screening. Toward this goal, I will employ
computational approaches to inform library design in order to increase the likelihood that library variants
effectively engage T cell receptors near the active site. I will employ next-generation sequencing to identify
lead candidates, which will then be rigorously evaluated via classic T cell activation assays. Finally, I will
critically analyze lead sequences in relationship to agonist activity in order to uncover potential molecular
determinants of agonist activity and structure-function relationships. Overall, the proposed research has the
potential for broad therapeutic impact given that insufficient cellular signaling is involved in a wide range of
pathologies including insufficient wound healing, autoimmune disease and cancer.
项目总结
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Agonist antibody discovery: Experimental, computational, and rational engineering approaches.
- DOI:10.1016/j.drudis.2021.09.008
- 发表时间:2022-01
- 期刊:
- 影响因子:7.4
- 作者:Schardt JS;Jhajj HS;O'Meara RL;Lwo TS;Smith MD;Tessier PM
- 通讯作者:Tessier PM
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John Samuel Schardt其他文献
John Samuel Schardt的其他文献
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{{ truncateString('John Samuel Schardt', 18)}}的其他基金
Activity-based discovery and optimization of agonist antibodies
基于活性的激动剂抗体的发现和优化
- 批准号:
10159090 - 财政年份:2020
- 资助金额:
$ 0.34万 - 项目类别:
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