Phage Display for Improved Peptide-Based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
基本信息
- 批准号:10343781
- 负责人:
- 金额:--
- 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 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AffinityAntibodiesAntigensBacteriophagesBindingBiological MarkersBloodBlood CirculationBreastBreast Cancer therapyCD44 geneCancer BiologyCancer DetectionCarbohydratesCell AdhesionCellsCessation of lifeChelating AgentsChemistryChemotherapy and/or radiationClinical TrialsCombined Modality TherapyComplexCoupledCyclooctenesDetectionDevelopmentDiagnosisDiseaseDoseDose-LimitingDrug KineticsDrug resistanceEstrogensExhibitsFemaleGalectin 3GenderGeneral PopulationGenomic medicineGenomicsGoalsHealthHealthcareHormonesHumanHydrophobicityImageImmune checkpoint inhibitorImmune responseImmunoglobulin FragmentsImmunologic SurveillanceIncidenceInjectionsKidneyLabelLaboratoriesLectinLigandsMalignant NeoplasmsMalignant neoplasm of prostateMammary NeoplasmsMetalsMissionMolecularMorbidity - disease rateMultimodal ImagingNeoplasm MetastasisNormal tissue morphologyNucleosome Core ParticleOrganPathway interactionsPatient CarePatientsPeptide FragmentsPeptide antibodiesPeptidesPhage DisplayPopulationProcessProgesteronePrognosisProstateProtein EngineeringRNA SplicingRadiation induced damageRadiation therapyRadioactiveRadioactivityRadiochemistryRadioimmunoconjugateRadiolabeledReactionRelapseResearchResistanceSignal PathwaySignal TransductionSilicon DioxideSurfaceT-Cell ReceptorTherapeuticTimeTissuesToxic effectTriad Acrylic ResinTumorigenicityUnited StatesVariantVeteransWomanWomen&aposs HealthWorkangiogenesisbasecancer imagingcancer stem cellcancer therapycancer typecheckpoint receptorscycloadditionerbB-2 Receptorglycosylationimaging agentimmune checkpointimmunogenicimmunoregulationimprovedin vivointerestirradiationmalignant breast neoplasmmilitary veteranmultimodalitynanoparticlenear infrared dyeneoplastic cellnoveloverexpressionprogrammed cell death protein 1radiotracerscaffoldsmall moleculestandard carestandard of carestem cell biomarkerssuccesstargeted agenttargeted imagingtargeted treatmenttheranosticstriple-negative invasive breast carcinomatumortumor growthtumorigenesistumorigenicuptake
项目摘要
Aggressive forms of cancer are a leading health problem for United States Veterans. While most cancers
are treatable in their earliest forms, gender-related cancers including those of the breast and prostate are
often fatal when diagnosed at advanced and/or metastatic stages. In 2020, these cancers will account for over
75,400 annual deaths in the general population, with morbidity rates significantly higher in the Veteran
population. While most patients initially respond to treatment, they often relapse and develop aggressive and
drug resistant tumors. A promising approach to better detect and treat these types of cancers may be through
development of agents that target drug resistance biomarkers that associate with cancer stem cells (CSCs).
CSCs make up a small proportion of a tumor but drive tumor aggressiveness and drug resistance. There are
few validated CSC biomarkers, and most are not cancer-specific. Our laboratory is at the forefront of new
biomarker and CSC identification using bacteriophage (phage) display. Peptides and antibody (Ab) fragments
that bind the breast and prostate associated Thomsen-Friedenreich carbohydrate antigen, (TF), the lectin
galectin-3 (gal-3) that binds TF and inhibits immune response, and CD444v6 have been obtained. These
antigens are involved in cell adhesion, angiogenesis, immune regulation, and cell signaling, and are thought to
represent CSC biomarkers. Further, we demonstrated that CD44v6 binds gal-3 through TF interaction,
suggesting this triad may represent a novel target to probe CSCs, tumor growth and immune surveillance.
Both Abs and peptides have been used with mixed success in cancer imaging and therapy. In terms of
Abs their large size can cause immunogenic problems and long distribution times that once radiolabeled often
leads to organ and tissue damage. Conversely, peptides, particularly those from phage display are
usually hydrophobic and often suffer from poor affinity and tumor uptake. Two different tacks will be
employed that overcome these drawbacks. A pretargeted “click” chemistry approach which decouples the
tumor-targeting step from the radioimaging or radiotherapy step can be employed. This pretargeted approach
is based on the rapid and highly specific cycloaddition reaction that occurs between the trans-cyclooctene
(TCO) on the tumor by allowing the unlabeled targeting Ab to circulate and bind the target. Subsequently,
injection of a small molecule radiolabeled probe with rapid pharmacokinetics and high affinity for the
pretargeted Ab, will result in higher tumor to normal tissue uptake ratios compared to direct labeled Abs. The
second tack will be to conjugate small peptides to a nanoparticle for multi-peptide display. Cornell prime dots
(C' dots) are a new and well-characterized nanoparticle platform that offer both multimodal-targeted imaging
and therapy, and multiplexing biomarker interrogation. C' dots are silica core-shell PEG nanoparticles that
exhibit favorable clearance from the blood and are primarily excreted through the kidney overcoming extended
circulation times. The tunable surface chemistries and favorable in vivo pharmacokinetics allow C' dots to
overcome many of the dose limiting toxicities associated with current monomolecular cancer therapeutics.
It is hypothesized that the Ab fragments and peptides that target gal-3/TF/CD44v6, coupled with
pretargeting and C'dot multivalent display, will produce theranostic agents for aggressive prostate (PCa) and
breast cancer (BCa). The objectives of this research are to develop: 1) radioimaging and radiotherapeutic
agents of aggressive PCa and BCa tumors, 2) probes that inhibit tumorigenesis leading to reduced
tumor growth and metastasis, and 3) bifunctional molecular therapeutics that increase tumor immune
response through dual targeting with gal-3 and immune checkpoint inhibitors.
Our work will positively impact VA healthcare in that we are developing new targeting agents for detection
and treatment of cancer that will be well tolerated in vivo. This work will help improve the lives of our Veterans
and coincides with BLR&D general goals and special interests of Women's Health and Genomic Medicine.
侵袭性癌症是美国退伍军人的主要健康问题。虽然大多数癌症
是可以治疗的,与性别有关的癌症,包括乳腺癌和前列腺癌
在诊断为晚期和/或转移时通常是致命的。到2020年,这些癌症将占到超过
普通人群中每年有75,400人死亡,退伍军人的发病率明显更高
人口。虽然大多数患者最初对治疗有反应,但他们经常复发并发展为侵袭性和
耐药肿瘤。一种更好地检测和治疗这些类型的癌症的有希望的方法可能是通过
针对与癌症干细胞(CSCs)相关的耐药生物标记物的药物的开发。
CSCs在肿瘤中只占很小的比例,但会推动肿瘤的侵袭性和耐药性。确实有
很少有有效的CSC生物标记物,而且大多数不是癌症特异性的。我们的实验室处于新技术的前沿
用噬菌体(噬菌体)展示技术鉴定生物标志物和CSC。多肽和抗体(Ab)片段
结合乳腺和前列腺相关的Thomsen-Friedenreich碳水化合物抗原(Tf)的凝集素
半乳糖凝集素-3(Galectin-3,GAL-3)与转铁蛋白(Tf)结合,抑制免疫反应,CD444v6已被发现。这些
抗原参与细胞黏附、血管生成、免疫调节和细胞信号传递,并被认为是
代表CSC生物标志物。进一步,我们证明CD44v6通过Tf相互作用与GAL-3结合,
提示该三联体可能是探索肿瘤干细胞、肿瘤生长和免疫监测的新靶点。
单抗和多肽在癌症成像和治疗中的应用效果参差不齐。就.而言
ABS体积过大会导致免疫原性问题和长时间的分布,而这些问题一旦被放射性标记,往往
会导致器官和组织受损。相反,多肽,特别是那些来自噬菌体展示的多肽是
通常是疏水性的,通常亲和力和肿瘤摄取能力较差。将有两种不同的策略
克服了这些缺点的雇员。一种预先确定目标的“点击”化学方法,它将
可采用放射成像或放射治疗步骤中的肿瘤靶向步骤。这种预先确定目标的方法
是基于反式环辛烯之间发生的快速和高度特异的环加成反应
(TCO)通过允许未标记的靶向抗体循环和结合靶标来抑制肿瘤的生长。后来,
注射一种具有快速药代动力学和高亲和力的小分子标记探针
与直接标记的抗体相比,预靶向抗体将导致更高的肿瘤组织对正常组织的摄取率。这个
第二个策略是将小肽连接到纳米颗粒上,以用于多肽展示。康奈尔素点
(C‘DOTS)是一种新的、特征良好的纳米颗粒平台,它提供了多模式靶向成像
和治疗,以及多路生物标记物讯问。C‘点是二氧化硅核壳结构的聚乙二醇纳米粒
从血液中表现出良好的清除性,并主要通过肾脏排泄,克服了延展
发行量。可调的表面化学成分和良好的体内药代动力学使C‘dots能够
克服与当前单分子癌症疗法相关的许多剂量限制毒性。
推测靶向GAL-3/Tf/CD44v6的抗体片段和多肽与
前靶向和C‘Dot多价展示,将生产用于侵袭性前列腺(PCa)和
乳腺癌(BCA)。这项研究的目的是发展:1)放射成像和放射治疗
侵袭性PCA和BCA肿瘤的药物,2)抑制肿瘤形成导致减少的探针
肿瘤生长和转移,以及3)增强肿瘤免疫的双功能分子疗法
通过GAL-3和免疫检查点抑制剂的双重靶向反应。
我们的工作将对退伍军人管理局医疗保健产生积极影响,因为我们正在开发用于检测的新靶向试剂
以及对体内耐受性良好的癌症的治疗。这项工作将有助于改善我们退伍军人的生活
与女性健康和基因组医学的BLR&D总目标和特殊利益不谋而合。
项目成果
期刊论文数量(0)
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SUSAN L DEUTSCHER其他文献
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{{ truncateString('SUSAN L DEUTSCHER', 18)}}的其他基金
Targeting TF/CD44v6 for In Vivo Nano-generated alpha-therapy of Ovarian Cancer
靶向 TF/CD44v6 用于卵巢癌体内纳米α疗法
- 批准号:
8769083 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Targeting TF/CD44v6 for In Vivo Nano-generated alpha-therapy of Ovarian Cancer
靶向 TF/CD44v6 体内纳米α疗法治疗卵巢癌
- 批准号:
8878206 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Multivalent Nanophage Engineered as Dual Receptor Cancer Theranostic Agents.
多价纳米噬菌体被设计为双受体癌症治疗剂。
- 批准号:
8569062 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Phage Display for Improved Peptide-based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
8263685 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Phage Display for Improved Peptide-Based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
10554256 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Phage Display for Improved Peptide-Based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
10115970 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Phage Display for Improved Peptide-based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
8398936 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Phage Display for Improved Peptide-Based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
9236073 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Phage Display for Improved Peptide-based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
8138754 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Improved Peptide-based Tumor Targeting Agents Using Phage Display
使用噬菌体展示改进基于肽的肿瘤靶向剂
- 批准号:
7775087 - 财政年份:2009
- 资助金额:
-- - 项目类别:
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