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: 10693126
• 负责人: Adrian Chrastina
• 金额: $ 41.47万
• 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/10693126
• 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; Circulation; Clinical; Data; Development; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; ERBB2 gene; Endothelial Cells; Endothelium; Engraftment; Glutathione; Human; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Maximum Tolerated Dose; Medicine; Metastatic breast cancer; Modeling; Molecular; Nature; Neoplasm Metastasis; Neoplasms in Vascular Tissue; 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; Treatment Efficacy; Tumor Tissue; Validation; Vascular Endothelial Cell; Woman; cancer diagnosis; chemotherapy; clinical application; clinical translation; clinically relevant; efficacy evaluation; efficacy validation; experimental study; human model; humanized antibody; immunoreactivity; improved; intravenous administration; intravital microscopy; malignant breast neoplasm; neoplastic cell; novel; novel therapeutics; personalized medicine; screening; targeted treatment; therapeutic evaluation; therapeutically effective; translational framework; translational therapeutics; 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.

乳腺癌是女性最常诊断的癌症，也是第二大死亡原因 女人之中。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，这种处于进展转移阶段的疾病仍然无法治愈，并且有治疗选择 给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、进入和渗透到实体瘤中，以及对患者的毒性。因此，要开发更多 乳腺癌有效且安全的治疗方法，需要实施高效的靶向给药 系统。肿瘤内皮细胞表面的小窝充当跨内皮运输系统， 主动将目标抗体从血液循环泵入肿瘤组织。我们的研究结果支持这一点 靶向小窝提供了一个快速泵送带有特定附着物的靶向抗体的平台 进入乳腺肿瘤的浓度大大超过血液中的最高水平。使用这些最近 研究结果表明，我们打算针对 DM1 美登木素生物碱的抗体药物偶联物 (ADC)，这是最有效的药物之一 抗癌药物靶向肿瘤内皮细胞小窝中的膜联蛋白 A1 的截短形式，以传递这种作用 有效治疗乳腺肿瘤内部的强大疗法。我们已经证明 AnnA1 表达于 人类肿瘤的脉管系统和小窝。最近，我们制备了针对 AnnA1 的人源化抗体 （hAnnA1）和我们的初步实验表明乳腺癌对 hAnnA1 与 DM1 缀合 (hAnnA1-DM1 ADC)。我们假设通过泵送靶向抗体 当DM1药物进入乳腺肿瘤时，小凹可以快速、特异性地积累这种治疗剂 在肿瘤内部，导致肿瘤破坏并显着降低毒性。我们提出以下具体目标： 目标 1. 生成 ADC 并对其进行表征。我们将与DM1药物共价制备一系列缀合物 使用不可切割和可切割接头连接至 hAnnA1 抗体。根据 Aim2 的筛选，我们 将生成具有选定连接化学的 THIOMAB hAnnA1。 目标 2. 筛选最佳接头化学、生产、验证和药代动力学分析 乳腺癌啮齿动物肿瘤模型中肿瘤血管小窝靶向 DM1 THIOMAB ADC。这些 研究将能够实施最佳连接化学来开发具有 DM1 位点特异性连接的 ADC。 目标 3. 评估肿瘤血管小窝靶向 DM1 ADC 在治疗中的疗效 乳腺癌的临床相关模型。临床相关原位模型的治疗研究 乳腺癌，包括移植到人类乳房中的人类肿瘤球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 HER2+ 模型，将提供 评估新型 hAnnA1-DM1 ADC 疗法的平台。拟议项目将有助于建立框架 用于治疗乳腺癌的肿瘤小窝靶向 ADC 的临床转化。