Tumor caveolae-targeted systemic therapy of breast cancer with antibody drug conjugates

使用抗体药物缀合物对乳腺癌进行肿瘤小窝靶向全身治疗

• 批准号: 10237875
• 负责人: Adrian Chrastina
• 金额: $ 42.32万
• 依托单位: PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237875
• 关键词: Active Biological Transport; Annexin A1; Antibodies; Antibody-drug conjugates; Antineoplastic Agents; Blood; Blood Circulation; Blood Vessels; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer therapy; Cause of Death; Caveolae; Chemistry; Clinical; Data; Development; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; ERBB2 gene; Endothelial Cells; Endothelium; Glutathione; Human; Intravenous; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Maximum Tolerated Dose; Medicine; Metastatic breast cancer; Modeling; Molecular; Nature; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Operating System; Organ; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Penetration; Pharmaceutical Preparations; Phase; Production; Publishing; Pump; Rattus; Regimen; Rodent; Safety; Series; Site; Solid Neoplasm; Specificity; Speed; Surface; System; Systemic Therapy; Therapeutic; Therapeutic Agents; Therapeutic Studies; Time; Tissues; Toxic effect; Translations; Treatment Efficacy; Tumor Tissue; Validation; Vascular Endothelial Cell; Woman; base; cancer diagnosis; chemotherapy; clinical application; clinical translation; clinically relevant; efficacy evaluation; efficacy validation; experimental study; human model; humanized antibody; immunoreactivity; improved; intravital microscopy; malignant breast neoplasm; neoplastic cell; novel; novel therapeutics; personalized medicine; screening; targeted treatment; therapeutic evaluation; treatment response; treatment strategy; tumor; vascular endothelium permeability

Breast cancer is the most commonly diagnosed cancer in women and is a second leading cause of death among woman. Despite the significant progress in molecular understanding and personalized therapies of breast cancer, this disease in progressed metastatic stage remains incurable and treatment options available to patients provide only modest survival benefit. Efficacy of existing systemic chemotherapy is limited in delivery, access and penetration into solid tumors, as well as by toxicity to patients. Thus, to develop more effective and safer therapies of breast cancer, it is necessary to implement an efficient targeted drug delivery system. Caveolae at the surface of tumor endothelial cells act as a transendothelial transport system that actively pumps targeted antibodies from the blood circulation into the tumor tissue. Our findings support that targeting caveolae provides a platform for rapid pumping of targeted antibodies with attached cargo specifically into breast tumors at concentrations greatly exceeding maximum levels in the blood. Using these recent findings, we intend to target antibody drug conjugates (ADC) of DM1 maytansinoid, one of the most potent anticancer drugs to target truncated form of Annexin A1 in tumor endothelial caveolae in order to deliver this powerful therapeutic effectively inside of breast tumors. We have demonstrated that AnnA1 is expressed in the vasculature and caveolae of human tumors. Recently, we have generated humanized antibody against AnnA1 (hAnnA1) and our preliminary experiments demonstrate strong therapeutic response of breast cancer to hAnnA1 conjugated to DM1 (hAnnA1-DM1 ADC). We hypothesize that by pumping targeted antibodies armed with DM1 drug into breast tumors, caveolae can rapidly and specifically accumulate this therapeutic agent inside tumors, leading to tumor destruction with significantly reduced toxicity. We propose these Specific Aims: Aim 1. To generate and characterize ADCs. We will prepare series of conjugates with DM1 drug covalently attached to hAnnA1 antibody using non-cleavable and cleavable linkers. Based on the screening in Aim2, we will generate THIOMAB hAnnA1 with select linker chemistry. Aim 2. Screening for optimal linker chemistry, production, validation and pharmacokinetic analysis of tumor vascular caveolae-targeted DM1 THIOMAB ADC in rodent tumor model of breast cancer. These studies will enable implementing optimal linker chemistry to develop ADC with site-specific attachment of DM1. Aim 3. Evaluation of therapeutic efficacy of the tumor vascular caveolae-targeted DM1 ADCs in clinically-relevant models of breast cancer. Therapeutic studies in clinically-relevant orthotopic models of breast cancer, including intravital microscopy model of human tumor spheroids engrafted into human breast tissue, and patient-derived breast cancer xenografts, including triple-negative and HER2+ models, will provide platform to evaluate novel hAnnA1-DM1 ADC therapy. The proposed project will help to establish framework for clinical translation of tumor-caveolae targeted ADC for treatment of breast cancer.

乳腺癌是女性最常见的癌症，也是第二大死亡原因 在女人中。尽管在分子理解和个性化治疗方面取得了重大进展， 乳腺癌，这种疾病在进展转移阶段仍然无法治愈，治疗选择可用 对患者仅提供适度的生存益处。现有全身化疗的疗效有限， 递送、进入和渗透到实体肿瘤中，以及对患者的毒性。因此，要发展更多 为了更有效、更安全地治疗乳腺癌，有必要实施高效的靶向药物输送 系统肿瘤内皮细胞表面的小窝作为跨内皮转运系统， 主动将靶向抗体从血液循环泵入肿瘤组织。我们的研究结果支持， 靶向小窝提供了一个平台， 进入乳腺肿瘤的浓度大大超过血液中的最大水平。利用这些最近 研究结果，我们打算靶向DM 1美登木素生物碱的抗体药物缀合物（ADC）， 抗癌药物靶向肿瘤内皮细胞小窝中截短形式的膜联蛋白A1， 在乳腺肿瘤内有效的治疗。我们已经证明，AnnA 1表达在 人肿瘤的脉管系统和小窝。最近，我们已经产生了针对AnnA 1的人源化抗体， （hAnnA 1）和我们的初步实验表明，乳腺癌的强治疗反应， 与DM 1缀合的hAnnA 1（hAnnA 1-DM 1 ADC）。我们假设通过注射有针对性的抗体 随着DM 1药物进入乳腺肿瘤，小窝可以迅速和特异性地积累这种治疗剂 在肿瘤内，导致肿瘤破坏，毒性显著降低。我们提出这些具体目标： 目标1。生成ADC并对其进行表征。我们将制备一系列与DM 1药物共价结合的偶联物 使用不可切割和可切割接头连接至hAnnA 1抗体。基于目标2中的筛选，我们 将产生具有选择的连接体化学的THIOMAB hAnnA 1。 目标2.筛选最佳接头化学，生产，验证和药代动力学分析 肿瘤血管小窝靶向DM 1 THIOMAB ADC在啮齿动物乳腺癌肿瘤模型中的应用这些 研究将能够实现最佳的连接体化学反应，以开发具有DM 1位点特异性连接的ADC。 目标3。评估肿瘤血管小窝靶向DM 1 ADC在肿瘤患者中的治疗功效 乳腺癌的临床相关模型。临床相关原位模型中的治疗研究 乳腺癌，包括移植到人乳腺中的人肿瘤球状体的活体显微镜模型 组织和患者来源的乳腺癌异种移植物，包括三阴性和HER 2+模型，将提供 评估新型hAnnA 1-DM 1 ADC疗法的平台。拟议项目将有助于建立框架 用于肿瘤-小窝靶向ADC的临床转化以治疗乳腺癌。