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(由申请人提供):单克隆抗体是破译基因或蛋白质功能的重要试剂,并且是治疗和诊断试剂的丰富来源。然而,使用抗碳水化合物抗体来靶向聚糖以达到这些目的却不太成功。聚糖比蛋白质或核酸含有更少的疏水功能,因此单个聚糖-抗体相互作用相对较弱。聚糖编码的信息通常涉及支链寡糖的细微变化,而传统抗体无法检测到这些变化。因此,很难获得能够完全了解生物聚糖功能的试剂。细胞表面聚糖组成的变化与癌症(和其他疾病状态)有关;因此,鉴定特异性和高亲和力聚糖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途径。我们建议开发使用新型抗体噬菌体展示技术来识别此类试剂的方法。最近,从噬菌体文库中选择几乎任何蛋白质抗原的特异性和高亲和力抗体已成为可能,这些噬菌体文库带有由合成 DNA 编码的定制多样性元素(“合成抗体”)。这一创新技术平台无需动物免疫,从而规避了传统杂交瘤方法的许多限制。我们将使用 2G12 的独特结构支架(一种针对 HIV-1 糖蛋白 gp120 上的寡甘露糖的抗体)作为我们设计的模板。 2G12 IgG 的两个重链可变结构域交换位置,以创建每个 IgG 分子包含四个寡甘露糖结合位点的扩展识别表面。我们开发了一种噬菌体载体,可以实现 2G12 支架的功能展示。我们将制备合成 2G12 抗体库,以确定该支架中高亲和力聚糖识别的最低理化要求。接下来,我们将利用从这些研究中获得的信息来识别新的 2G12 变体,这些变体对肿瘤相关聚糖靶点具有改变的特异性。这一创新策略将产生新型癌症抗体,加速癌症研究,并为新癌症疗法和诊断的开发铺平道路。
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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