Pharmacokinetic strategies to increase monoclonal antibody uptake, distribution, and efficacy for treatment of solid tumors
增加单克隆抗体摄取、分布和治疗实体瘤疗效的药代动力学策略
基本信息
- 批准号:10164739
- 负责人:
- 金额:$ 36.27万
- 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:2020-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AffinityAntibodiesAntibody AffinityAntibody TherapyAntibody-drug conjugatesAntigensBindingBinding SitesBiologicalBlood VesselsBreastBypassCancer PatientCarcinoembryonic AntigenCatabolismCell Surface ReceptorsCessation of lifeCetuximabCharacteristicsChimeric ProteinsClostridiumCollagenColorectal CancerConvectionDataDevelopmentDiffuseDissociationDrug KineticsERBB2 geneEndosomesEnzymesEvaluationExocytosisExtracellular FluidExtracellular MatrixExtravasationGemtuzumab OzogamicinHealthHematologic NeoplasmsHumanImmunoglobulin FragmentsIn VitroIncidenceInjectionsIntercellular FluidInvestigationLungLymphangiogenesisMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMediatingModelingMonoclonal AntibodiesOncologyPatientsPharmaceutical PreparationsPhysiologicalPrevalenceProstateSafetySiteSolid NeoplasmSyndromeTestingTherapeutic Monoclonal AntibodiesTranslationsTrastuzumabTreatment EfficacyTumor AntibodiesTumor AntigensUnited StatesVascularizationWorkanti-cancercancer diagnosiscancer therapycell growthchemotherapycollagenasedesignhuman cancer mouse modelhuman modelimprovedin silicoin vivomalignant breast neoplasmmalignant stomach neoplasmmathematical modelmodels and simulationmouse modelnanobodiesneonatal Fc receptornovelnovel strategiespressurepreventreceptor mediated endocytosisresearch clinical testingrituximabside effecttargeted cancer therapytargeted deliverytreatment optimizationtumoruptake
项目摘要
Although advances have been made in the treatment of cancer, therapy is inadequate for many patients, and it
is projected that there will be over 607,000 cancer deaths in the US in 2019. Many of these deaths will result
from cancers that develop as solid tumors, which are particularly difficult to treat with chemotherapy or with
biological drugs. Sub-optimal efficacy of anti-cancer monoclonal antibodies (mAb) and antibody-drug conjugates
(ADC) has been explained, in part, by poor uptake and distribution of these agents within solid tumors.
Pathophysiologic characteristics of solid tumors include their chaotic cellular growth, dense extracellular
matrices, poor and disorganized vascularization, decreased lymphangiogenesis, and high interstitial fluid
pressure. These characteristics limit the convective and diffusive transport of mAb and ADC within tumors,
leading to poor and heterogeneous intra-tumoral distribution. This proposal tests three new platform strategies
designed to improve the selectivity and efficacy of anti-cancer monoclonal antibody-based therapy by enhancing
the distribution of mAb and ADCs within solid tumors. Aim #1 introduces a novel strategy for overcoming the
“binding-site barrier” within tumors through transient inhibition of antibody binding to antigen, as achieved co-
administration of anti-idiotypic agents that allow short-term and reversible antagonism of mAb binding. Aim #2
will investigate the use of antibodies with pH-dependent, “catch-and-release” binding to bypass the catabolic
sink associated with receptor-mediated endocytosis of anti-cancer mAb. In Aim #3, targeted delivery of matrix-
modulating enzymes will be employed to achieve selective depletion of collagen in tumors, and to enable
improved intra-tumoral distribution of mAb and ADC. Each aim is strongly supported by mechanistic
mathematical modeling and by preliminary data demonstrating utility and feasibility. Pharmacokinetics, efficacy,
and safety of optimized anti-HER2 mAb and ADC therapy will be assessed using mouse models of HER2-
positive human cancer. The novel agents developed in this work may be suitable for immediate translation toward
optimization of trastuzumab and ado-trastuzumab emtansine treatment of HER2-positive breast and gastric
cancer patients. Additionally, the approaches introduced in this proposal may be extended for use in optimizing
therapy with all mAb and ADC applied to the treatment of solid tumors, potentially providing benefit to hundreds
of thousands of patients.
尽管在癌症治疗方面取得了进展,但对许多患者来说,治疗方法还不够,而且这种治疗方法也不太有效
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph P Balthasar其他文献
Joseph P Balthasar的其他文献
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{{ truncateString('Joseph P Balthasar', 18)}}的其他基金
Pharmacokinetic / Pharmacodynamic Optimization of ADC Therapy for Acute Myeloid Leukemia
急性髓系白血病 ADC 治疗的药代动力学/药效学优化
- 批准号:
10561230 - 财政年份:2023
- 资助金额:
$ 36.27万 - 项目类别:
Enhancement of ADC selectivity by inverse targeting: Mechanistic studies and optimization
通过反向靶向增强 ADC 选择性:机理研究和优化
- 批准号:
10415220 - 财政年份:2021
- 资助金额:
$ 36.27万 - 项目类别:
Enhancement of ADC selectivity by inverse targeting: Mechanistic studies and optimization
通过反向靶向增强 ADC 选择性:机理研究和优化
- 批准号:
10312178 - 财政年份:2021
- 资助金额:
$ 36.27万 - 项目类别:
Enhancement of ADC selectivity by inverse targeting: Mechanistic studies and optimization
通过反向靶向增强 ADC 选择性:机理研究和优化
- 批准号:
10623301 - 财政年份:2021
- 资助金额:
$ 36.27万 - 项目类别:
Pharmacokinetic strategies to increase monoclonal antibody uptake, distribution, and efficacy for treatment of solid tumors
增加单克隆抗体摄取、分布和治疗实体瘤疗效的药代动力学策略
- 批准号:
10623152 - 财政年份:2020
- 资助金额:
$ 36.27万 - 项目类别:
Pharmacokinetic strategies to increase monoclonal antibody uptake, distribution, and efficacy for treatment of solid tumors
增加单克隆抗体摄取、分布和治疗实体瘤疗效的药代动力学策略
- 批准号:
10397091 - 财政年份:2020
- 资助金额:
$ 36.27万 - 项目类别:
Catch and Release Immunotoxins: CAR-Bombs for Cancer
捕获并释放免疫毒素:治疗癌症的 CAR 炸弹
- 批准号:
10062878 - 财政年份:2016
- 资助金额:
$ 36.27万 - 项目类别:
Pharmacokinetic strategies to optimize IP chemotherapy
优化IP化疗的药代动力学策略
- 批准号:
7144306 - 财政年份:2006
- 资助金额:
$ 36.27万 - 项目类别:
Pharmacokinetic strategies to optimize IP chemotherapy
优化IP化疗的药代动力学策略
- 批准号:
7646274 - 财政年份:2006
- 资助金额:
$ 36.27万 - 项目类别:
Pharmacokinetic strategies to optimize IP chemotherapy
优化IP化疗的药代动力学策略
- 批准号:
7286074 - 财政年份:2006
- 资助金额:
$ 36.27万 - 项目类别:
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