Development of caveolae-targeted antibody-drug conjugates
开发小凹靶向抗体药物偶联物
基本信息
- 批准号:10251313
- 负责人:
- 金额:$ 43.97万
- 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:AddressAffinityAnnexin A1AntibodiesAntibody-drug conjugatesAntineoplastic AgentsAttenuatedBT 474BindingBiodistributionBiologicalBiometryBloodBlood VesselsBreast Cancer CellBreast Cancer TreatmentBuffersCancer ModelCarboplatinCaveolaeCell WallCell surfaceChemistryCisplatinCleaved cellClinicComplexDataData AnalysesDevelopmentDextransDisseminated Malignant NeoplasmDoseDrug Delivery SystemsDrug KineticsDrug resistanceEndothelial CellsEndotheliumGoalsHalf-LifeHistologyHumanImageImmunoconjugatesIn VitroInjectionsIntravenousKineticsMDA MB 231Mammary NeoplasmsMaximum Tolerated DoseMeasuresMetastatic Neoplasm to the LungMetastatic breast cancerModelingModernizationMonitorMulti-Drug ResistanceMultimodal ImagingMusNeoplasm MetastasisNormal tissue morphologyPathway interactionsPatientsPenetrationPharmaceutical PreparationsPhasePlasmaPlatinumPre-Clinical ModelPropertyProteinsPublishingPumpQuality ControlRattusRiskRodentSafetyServicesSideSolidSolid NeoplasmSolubilitySpecificitySpeedSystemTestingTherapeuticToxic effectTranslatingTranslationsTreatment EfficacyVascular Endothelial CellVascular EndotheliumX-Ray Computed Tomographyanimal imagingbasecGMP productioncancer therapycarboxylatecarcinogenicitychemotherapyclinical candidateclinical efficacyclinical translationdesigndosagedrug efficacyhumanized antibodyimprovedin vivoinnovationintravital microscopylung metastaticmalignant breast neoplasmneoplastic cellnovelnovel therapeuticsoxaliplatinpatient derived xenograft modelpre-clinicalreplication factor Cresearch clinical testingresponseside effectsingle photon emission computed tomographysystemic toxicitytargeted deliverytargeted treatmenttherapeutic effectivenesstherapy outcometreatment responsetumoruptakevascular endothelium permeability
项目摘要
PROJECT 2 SUMMARY
The overall objective of the Project 2 is to utilize a newly discovered, active transendothelial transport pathway,
the caveolae pumping system, in order to provide an effective solution to the delivery and toxicity problem of
chemotherapeutics in metastatic breast cancer treatment. In order to address these problems and significantly
improve therapeutic outcome we propose to develop novel antibody-drug conjugates (ADCs) that exploit our
newly discovered endothelial cell (EC) caveolae targeting system in order to sidestep passive delivery problem
of modern chemotherapeutics. We have established that EC caveolae in preclinical models can rapidly and
specifically pump anti-Annexin A1 antibodies and attached cargo across the vascular endothelial barrier
directly into solid tumors. Based on this discovery, we propose to design novel EC caveolae-targeted ADCs for
greatly enhanced efficacy in tumor destruction in breast cancer. Our main hypothesis is that
immunoconjugates that fully utilize the advantages of the EC caveolae-pumping system will dramatically
increase delivery of chemotherapeutic drugs into tumors, thereby requiring much lower dosages and
dramatically enhancing efficacy of treatment. This hypothesis will be tested by the following specific aims: In
Aim 1, we will design and synthesize Pt(II)-carboxymethyl dextran (CMD) ADCs and optimize carboxylate
derivatization of CMD, conjugation chemistry, and Pt(II) loading in order to maximize binding affinity toward
human Annexin A1 protein. We will test and optimize physicochemical properties, stability on storage, in
human plasma, and Pt(II) release kinetics in the tumor interstitium. In Aim 2 we will assess therapeutic efficacy
of the ADCs in metastatic cancer models. The efficacy of our targeted delivery system will be examined in
MDA-231-LM2-4, and rat tumor models with 13762 breast cancer cells metastasized to lung using whole-body
animal imaging with X-ray/CT. In Aim 3 we will examine the therapeutic efficacy of the ADCs in tumors with
human blood vessels using intravital microscopy (IVM). We will monitor tumor size in response to therapy in
human-on-human IVM model using BT-474 tumor spheroids, and in patient-derived xenografts (PDX) IVM
model. In this Aim we will also translate our select preclinical candidate for clinical testing, where successful
targeted therapeutic will be selected as clinical candidates for cGMP production (Core B) for subsequent
testing in a Phase 1 safety trial in Project 3. Antibodies for conjugation to form ADCs will be provided by Core
B. Core B will also provide quality control analysis of ADCs and confirmation of antibody binding affinity
following conjugation. Tumor targeting, delivery and accumulation of these novel therapies will be assessed in
rodents using multi-modality imaging services provided by Core C, which includes X-ray/CT, SPECT-CT, IVM,
and histology. Core E will handle the biostatistical analysis of data generated during the course of the project.
The long-term goal is to translate our key basic discoveries into unique, innovative delivery platform in order to
improve therapeutic efficacy of human cancer therapy.
项目2概要
项目2的总体目标是利用新发现的主动跨内皮转运途径,
为了提供一种有效的解决输送和毒性问题的方法,
转移性乳腺癌治疗中的化学治疗剂。为了解决这些问题,
改进治疗结果我们提出开发新的抗体-药物缀合物(ADC),其利用我们的
一种新发现的内皮细胞(EC)小窝靶向系统,以避免被动递送问题
现代化学疗法。我们已经确定,在临床前模型中,EC小窝可以快速,
特异性泵送抗膜联蛋白A1抗体和附着的货物穿过血管内皮屏障
直接植入实体瘤基于这一发现,我们提出设计新型EC小窝靶向ADC,
大大增强了乳腺癌中肿瘤破坏的功效。我们的主要假设是
充分利用EC小窝泵送系统的优点的免疫缀合物将显著地
增加化疗药物向肿瘤中的递送,从而需要低得多的剂量,
大大提高了治疗效果。这一假设将通过以下具体目标进行检验:
目标1,设计合成Pt(II)-羧甲基葡聚糖(CMD)ADC并优化羧酸盐
CMD的衍生化、缀合化学和Pt(II)负载,以最大化对
人膜联蛋白A1蛋白。我们将测试和优化理化性质,储存稳定性,
人血浆和肿瘤组织中Pt(II)的释放动力学。在目标2中,我们将评估治疗效果
ADC在转移性癌症模型中的作用。我们的靶向给药系统的疗效将在
MDA-231-LM 2 -4和使用全身给药的具有13762个乳腺癌细胞转移到肺的大鼠肿瘤模型
X线/CT动物成像。在目标3中,我们将检查ADC在具有以下特征的肿瘤中的治疗功效:
使用活体显微镜(IVM)的人血管。我们将监测肿瘤的大小,以应对治疗,
使用BT-474肿瘤球状体的人对人IVM模型,以及在患者来源的异种移植物(PDX)IVM中
模型在这个目标中,我们还将翻译我们选择的临床前候选药物进行临床试验,如果成功的话,
将选择靶向治疗剂作为cGMP生产的临床候选物(核心B),用于随后的
在项目3的1期安全性试验中进行测试。用于缀合以形成ADC的抗体将由核心抗体库提供。
B。核心B还将提供ADC的质量控制分析和抗体结合亲和力的确认
在共轭之后。这些新疗法的肿瘤靶向、递送和累积将在
啮齿动物使用Core C提供的多模态成像服务,包括X射线/CT、SPECT-CT、IVM,
和组织学。核心E将处理项目过程中生成的数据的生物统计分析。
长期目标是将我们的关键基础发现转化为独特的创新交付平台,
提高人类癌症治疗疗效。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Bogdan Olenyuk其他文献
Bogdan Olenyuk的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Bogdan Olenyuk', 18)}}的其他基金
Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer
内皮细胞靶向鹅膏毒素缀合物可有效治疗乳腺癌
- 批准号:
10439623 - 财政年份:2019
- 资助金额:
$ 43.97万 - 项目类别:
Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer
内皮细胞靶向鹅膏毒素缀合物可有效治疗乳腺癌
- 批准号:
10197859 - 财政年份:2019
- 资助金额:
$ 43.97万 - 项目类别:
Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer
内皮细胞靶向鹅膏毒素缀合物可有效治疗乳腺癌
- 批准号:
10653843 - 财政年份:2019
- 资助金额:
$ 43.97万 - 项目类别:
Development of caveolae-targeted antibody-drug conjugates
开发小凹靶向抗体药物偶联物
- 批准号:
9974488 - 财政年份:2019
- 资助金额:
$ 43.97万 - 项目类别:
Development of caveolae-targeted antibody-drug conjugates
开发小凹靶向抗体药物偶联物
- 批准号:
10655403 - 财政年份:2019
- 资助金额:
$ 43.97万 - 项目类别:
Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer
内皮细胞靶向鹅膏毒素缀合物可有效治疗乳腺癌
- 批准号:
9803487 - 财政年份:2019
- 资助金额:
$ 43.97万 - 项目类别:
Development of caveolae-targeted antibody-drug conjugates
开发小凹靶向抗体药物偶联物
- 批准号:
10449306 - 财政年份:2019
- 资助金额:
$ 43.97万 - 项目类别:
Active Delivery of Platinum Nanoimmunoconjugates to Improve Breast Cancer Therapy
主动递送铂纳米免疫缀合物以改善乳腺癌治疗
- 批准号:
9893830 - 财政年份:2017
- 资助金额:
$ 43.97万 - 项目类别:
Active Delivery of Platinum Nanoimmunoconjugates to Improve Breast Cancer Therapy
主动递送铂纳米免疫缀合物以改善乳腺癌治疗
- 批准号:
10249060 - 财政年份:2017
- 资助金额:
$ 43.97万 - 项目类别:
Small Molecule Protein Ligands as Modulators of Hypoxia-Inducible Transcription
小分子蛋白配体作为缺氧诱导转录的调节剂
- 批准号:
8865244 - 财政年份:2015
- 资助金额:
$ 43.97万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 43.97万 - 项目类别:
Continuing Grant