Methods to Identify High-Affinity Antibodies that Target Tumor-Associated Glycans
鉴定针对肿瘤相关聚糖的高亲和力抗体的方法
基本信息
- 批准号:8504989
- 负责人:
- 金额:$ 19.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmino AcidsAnimal SourcesAnimalsAntibodiesAntibody AffinityAntibody DiversityAntibody FormationAntigensArchitectureBacteriophagesBenchmarkingBindingBinding SitesBioinformaticsBiologicalBiological ProcessCancer DiagnosticsCase StudyCell surfaceChemicalsCloningCodon NucleotidesComplementarity Determining RegionsDNA Sequence RearrangementDevelopmentDiagnosisDiagnosticDiagnostic ReagentDiseaseDissociationElementsEvaluationEventGlycoproteinsGoalsHIV Envelope Protein gp120HIV-1HumanHybridomasImmunizationImmunoglobulin GIndividualLibrariesMalignant NeoplasmsMethodologyMethodsMonoclonal AntibodiesMusNucleic AcidsOligonucleotidesOligosaccharidesPeptidesPhage DisplayPlant RootsPlayPolysaccharidesPositioning AttributeProductionPropertyProteinsRandomizedReagentReportingResearchRoleSourceSpecificitySurfaceTechniquesTechnologyTherapeuticUrsidae FamilyVariantanticancer researchbasecancer therapychemotherapydesigngene functionhumanized antibodyimmunogenicinnovationinnovative technologiesinsightnovelprotein functionscaffoldsynthetic constructtargeted deliverytooltumortumorigenesisvector
项目摘要
DESCRIPTION (provided by applicant): Monoclonal antibodies are essential reagents for deciphering gene or protein function and have been a fruitful source of therapeutic and diagnostic agents. However, the use of anticarbohydrate antibodies to target glycans for these purposes has been less successful. Glycans contain less hydrophobic functionality than do proteins or nucleic acids, thus individual glycan-antibody interactions are relatively weak. Information encoded by glycans often involves subtle variations of branched oligosaccharides that cannot be detected with conventional antibodies. It has therefore been difficult to obtain reagents that enable a complete understanding of biological glycan function. Changes in cell surface glycan composition are associated with cancer (and other disease states); therefore, general methods to identify specific and high- affinity glycan antibodies would greatly facilitate cancer research and provide new avenues for cancer therapies and diagnostics. We propose to develop methods to identify such reagents using novel antibody phage display technologies. It has recently become possible to select specific and high affinity antibodies for virtually any protein antigen from phage libraries that bear tailored diversity elements encoded by synthetic DNA ('synthetic antibodies'). This innovative technology platform obviates the requirement for animal immunization, thereby circumventing many limitations of traditional hybridoma methods. We will use the unique architectural scaffold of 2G12, an antibody that targets oligomannoses on the HIV-1 glycoprotein gp120, as the template for our design. The two heavy chain variable domains of 2G12 IgG exchange positions to create an extended recognition surface containing four oligomannose binding sites per IgG molecule. We have developed a phage vector that allows the functional display of the 2G12 scaffold. We will prepare synthetic 2G12 antibody libraries to determine minimal physicochemical requirements for high affinity glycan recognition in this scaffold. Next, we will use the information gained from these studies to identify novel 2G12 variants with altered specificity profiles for tumor-associated glycan targets. This innovative strategy will result in novel cancer antibodies that accelerate cancer research and pave the way for development of new cancer therapies and diagnostics.
描述(申请人提供):单抗是破译基因或蛋白质功能的基本试剂,是治疗和诊断试剂的丰富来源。然而,为了这些目的而使用抗碳水化合物抗体来靶向糖链的研究就不那么成功了。与蛋白质或核酸相比,葡聚糖含有较少的疏水功能,因此单个糖链与抗体的相互作用相对较弱。用多聚糖编码的信息通常涉及用常规抗体无法检测到的分枝低聚糖的细微变化。因此,很难获得能够完全了解生物多糖功能的试剂。细胞表面糖链组成的变化与癌症(和其他疾病状态)有关;因此,鉴定特异性和高亲和力的糖链抗体的通用方法将极大地促进癌症研究,并为癌症治疗和诊断提供新的途径。我们建议开发使用新型抗体噬菌体展示技术来鉴定这类试剂的方法。最近已经有可能从带有由合成DNA(合成抗体)编码的定制多样性元件的噬菌体库中选择针对几乎任何蛋白质抗原的特异性和高亲和力抗体。这一创新的技术平台避免了对动物免疫的要求,从而绕过了传统杂交瘤方法的许多局限性。我们将使用2G12的独特结构支架作为我们设计的模板,2G12是一种针对HIV-1糖蛋白gp120上的寡聚注释的抗体。2G12免疫球蛋白的两个重链可变区交换位置,形成一个延伸的识别表面,每个免疫球蛋白分子包含四个寡核苷酸结合部位。我们开发了一种噬菌体载体,可以展示2G12支架的功能。我们将准备合成的2G12抗体库,以确定在这种支架上识别高亲和力多糖所需的最低物理化学要求。接下来,我们将使用从这些研究中获得的信息来识别具有肿瘤相关糖链靶标特异性改变的新型2G12变异体。这一创新战略将产生新的癌症抗体,加速癌症研究,并为新的癌症治疗和诊断方法的开发铺平道路。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A strategy for phage display selection of functional domain-exchanged immunoglobulin scaffolds with high affinity for glycan targets.
噬菌体展示选择对聚糖靶标具有高亲和力的功能域交换免疫球蛋白支架的策略。
- DOI:10.1016/j.jim.2011.12.008
- 发表时间:2012
- 期刊:
- 影响因子:2.2
- 作者:Stewart,Alex;Liu,Yanyun;Lai,JonathanR
- 通讯作者:Lai,JonathanR
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Jonathan R. Lai其他文献
The alphavirus determinants of intercellular long extension formation
细胞间长延伸形成的甲病毒决定因素
- DOI:
10.1128/mbio.01986-24 - 发表时间:
2024-12-17 - 期刊:
- 影响因子:4.700
- 作者:
Caroline K. Martin;Judy J. Wan;Peiqi Yin;Thomas E. Morrison;William B. Messer;Vanessa Rivera-Amill;Jonathan R. Lai;Nina Grau;Félix A. Rey;Thérèse Couderc;Marc Lecuit;Margaret Kielian - 通讯作者:
Margaret Kielian
A two-component cocktail of engineered DIII nanoparticles elicits broadly neutralizing antibody responses against dengue virus in mice
一种由工程化DIII纳米颗粒组成的双组分鸡尾酒在小鼠中引发了针对登革热病毒的广泛中和抗体反应
- DOI:
10.1016/j.isci.2025.112534 - 发表时间:
2025-06-20 - 期刊:
- 影响因子:4.100
- 作者:
Margarette C. Mariano;Helen S. Jung;Olivia Vergnolle;Keith Haskell;Lamount R. Evanson;Gregory Quevedo;Julia C. Frei;Karen Tong;Larissa B. Thackray;Michael S. Diamond;Jonathan R. Lai - 通讯作者:
Jonathan R. Lai
Jonathan R. Lai的其他文献
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{{ truncateString('Jonathan R. Lai', 18)}}的其他基金
Developing a new bispecific antibody mimicking rapid antigen-specific memory CD8+ T cell-mediated protection
开发一种新型双特异性抗体,模仿快速抗原特异性记忆 CD8 T 细胞介导的保护
- 批准号:
10742118 - 财政年份:2023
- 资助金额:
$ 19.54万 - 项目类别:
Structure-based design of broad flavivirus immunogens
广泛黄病毒免疫原的基于结构的设计
- 批准号:
10494281 - 财政年份:2021
- 资助金额:
$ 19.54万 - 项目类别:
Eliciting and isolating neutralizing antibodies against Powassan virus
引发并分离针对波瓦桑病毒的中和抗体
- 批准号:
10459523 - 财政年份:2021
- 资助金额:
$ 19.54万 - 项目类别:
Eliciting and isolating neutralizing antibodies against Powassan virus
引发并分离针对波瓦桑病毒的中和抗体
- 批准号:
10290425 - 财政年份:2021
- 资助金额:
$ 19.54万 - 项目类别:
Structure-based design of broad flavivirus immunogens
广泛黄病毒免疫原的基于结构的设计
- 批准号:
10390845 - 财政年份:2021
- 资助金额:
$ 19.54万 - 项目类别:
Structure-based design of broad flavivirus immunogens
广泛黄病毒免疫原的基于结构的设计
- 批准号:
10685350 - 财政年份:2021
- 资助金额:
$ 19.54万 - 项目类别:
Engineered Dengue EDIIIs as Broad Immunogens
作为广泛免疫原的工程登革热 EDIII
- 批准号:
9224550 - 财政年份:2017
- 资助金额:
$ 19.54万 - 项目类别:
Methods to Identify High-Affinity Antibodies that Target Tumor-Associated Glycans
鉴定针对肿瘤相关聚糖的高亲和力抗体的方法
- 批准号:
8294534 - 财政年份:2011
- 资助金额:
$ 19.54万 - 项目类别:
Methods to Identify High-Affinity Antibodies that Target Tumor-Associated Glycans
鉴定针对肿瘤相关聚糖的高亲和力抗体的方法
- 批准号:
8034536 - 财政年份:2011
- 资助金额:
$ 19.54万 - 项目类别:
Targeting Viral Envelope Glycoproteins with Synthetic Antibodies
用合成抗体靶向病毒包膜糖蛋白
- 批准号:
7952441 - 财政年份:2010
- 资助金额:
$ 19.54万 - 项目类别:
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