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

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.
项目二总结

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Bogdan Olenyuk其他文献

Bogdan Olenyuk的其他文献

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{{ 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:

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