Precision Delivery and Imaging to Enhance Solid Tumor Therapy
精准输送和成像增强实体瘤治疗
基本信息
- 批准号:9974485
- 负责人:
- 金额:$ 266.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-08 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Active Biological TransportAnnexin A1AntibodiesAntibody-drug conjugatesAntineoplastic AgentsBindingBiodistributionBlood VesselsBypassCancer PatientCaveolaeCellsCisplatinClinicClinicalClinical TrialsCyclic GMPCytotoxic agentDevelopmentDiagnosticDiseaseDisseminated Malignant NeoplasmDoseDrug Delivery SystemsDrug resistanceEndothelial CellsEndotheliumEnvironmentExhibitsGenesGoalsGrantHematologic NeoplasmsHumanImageImmunoconjugatesLesionLife StyleLungMalignant NeoplasmsMammary NeoplasmsMediatingModelingMolecularMulti-Drug ResistanceNeoplasm MetastasisPathway interactionsPatientsPenetrationPharmaceutical PreparationsPharmacotherapyPhasePhase I Clinical TrialsPlatinumPre-Clinical ModelPreclinical TestingPreventionPrimary NeoplasmProgram Research Project GrantsPumpRadiation therapyRadiolabeledSafetySolidSolid NeoplasmSurfaceSystemTestingTherapeuticTherapeutic AgentsTherapeutic IndexTissuesToxic effectToxicologyTranslatingTreatment EfficacyTumor TissueVascular EndotheliumWarWorkantibody conjugatebasecancer imagingcancer therapychemoradiationchemotherapycytotoxicdisease diagnosisdosagedrug efficacydrug sensitivityexpectationfirst-in-humanimaging agentimaging studyimprovedin vivoindividual patientintravenous injectionmolecular targeted therapiesnovelnovel therapeuticspatient variabilitypre-clinicalprecision drugsprecision medicineprecision oncologyprogramsresearch clinical testingtargeted imagingtargeted treatmenttooltreatment optimizationtumor
项目摘要
PROJECT 1 SUMMARY
Existing antibody-based interventions for cancer rely on passive delivery of the circulating
drug that depends on a large concentration gradient across the semi-permeable wall of
blood vessels to get inside tumors. The forces driving the drug from the bloodstream into
tumors result in sub-optimal delivery and poor access to tumor cells, in part because
endothelial cells (EC) forming the vascular wall constitute a significant, limiting barrier.
We intend to boost precision delivery into primary and metastatic tumors by overcoming
the vascular EC barrier through a highly precise, active transport pathway that we
discovered through proteomic imaging and named the caveolae pumping system. The
approach proposed here to enhance delivery goes well beyond typical so- called 'active
targeting' of antibodies. Our lead humanized antibody against Annexin A1 (hAnnA1), a
tumor- specific antibody concentrated in EC caveolae, not only binds its intended target
but is actually the first antibody to penetrate solid tumors actively, rapidly and specifically.
It does so even at very low dosages and reaches unprecedented intra-tumoral
concentrations well beyond the highest blood levels after injection. It is now time to test
this unprecedented immunotargeting in humans. We propose here to develop a
radiolabeled humanized mAnnA1 to detect and destroy primary and metastatic lesions.
Major aims of this project are to: 1-2) evaluate in vivo delivery and efficacy of novel
caveolae-targeting radioimmunoconjugates in hard-to-treat metastatic tumor models of
breast cancer; 3) test the effectiveness of caveolae pumping in human tumor blood
vessels using PDX and novel human IVM tumor models; and translate hAnnA1 towards
clinical testing. We will 4) determine here the degree to which caveolae can be targeted
to pump radiolabeled antibodies across vascular EC to concentrate them inside solid
tumors as means to improve image-guided drug delivery and enhance
their efficacy. Antibodies will be provided by Core B and radiolabeled with assistance
provided by Core D for preclinical work. Several mammary tumor models will be used to
assess the ability of radiolabeled hAnnA1 to target primary and metastatic tumors via
imaging services provided in Core C. We will study by intravenously injected hAnnA1 with
advanced multimodality in vivo imaging to quantify and optimize precision transvascular
delivery and tumor penetration. As the utility of caveolae targeting in humans requires
AnnA1 expression in tumor EC caveolae, we will use Core C imaging services to compare
vascular expression of AnnA1 in preclinical tumor models and human tumors. To translate
our findings for clinical testing, we will test hAnnA1, humanize further if needed and
partner with NCI's NExT program for cGMP production, quality control and toxicology of
hAnnA1. With Core D, Project 3 will optimize hAnnA1 radiolabeling necessary to conduct
a first-in-human imaging trial as a direct result of successful translation of our findings
from Project 1 into the clinic.
项目1总结
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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Jan Eugeniusz Schnitzer其他文献
Jan Eugeniusz Schnitzer的其他文献
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{{ truncateString('Jan Eugeniusz Schnitzer', 18)}}的其他基金
Bispecific immunotherapeutic delivery system for lung diseases
用于肺部疾病的双特异性免疫治疗递送系统
- 批准号:
10720773 - 财政年份:2023
- 资助金额:
$ 266.71万 - 项目类别:
Precision Delivery and Imaging to Enhance Solid Tumor Therapy
精准输送和成像增强实体瘤治疗
- 批准号:
10655399 - 财政年份:2019
- 资助金额:
$ 266.71万 - 项目类别:
Precision Delivery and Imaging to Enhance Solid Tumor Therapy
精准输送和成像增强实体瘤治疗
- 批准号:
10449304 - 财政年份:2019
- 资助金额:
$ 266.71万 - 项目类别:
Precision Antibody Imaging & Radiotherapy of Solid Tumors
精密抗体成像
- 批准号:
10655400 - 财政年份:2019
- 资助金额:
$ 266.71万 - 项目类别:
Precision Antibody Imaging & Radiotherapy of Solid Tumors
精密抗体成像
- 批准号:
10251312 - 财政年份:2019
- 资助金额:
$ 266.71万 - 项目类别:
Precision Antibody Imaging & Radiotherapy of Solid Tumors
精密抗体成像
- 批准号:
9974487 - 财政年份:2019
- 资助金额:
$ 266.71万 - 项目类别:
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