HER2-pretargeting image-guided therapy of breast cancer

HER2 预靶向图像引导乳腺癌治疗

基本信息

批准号：
9301787
负责人：
Dmitri Artemov
金额：
$ 40.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301787
关键词：
Address Adjuvant Affinity Albumins Animals Antibodies Antibody-drug conjugates Area BT 474 Binding Biodistribution Biopsy Bispecific Antibodies Blood Circulation Breast Cancer Cell Breast Cancer Detection Breast Cancer Model Breast Cancer therapy Carrier Proteins Cells Cessation of life Chemistry Clinical Cytotoxic agent Decision Making Diagnosis Disease Disease remission Dose Drug Carriers ERBB2 gene Endocrine Ensure Epithelial Cells Future Gold Hepatocyte Human Immune Immune response Immunocompetent In Situ In Vitro Kinetics Label Lesion Ligation MCF10A cells MCF7 cell MDA MB 231 Malignant Neoplasms Mammary Neoplasms Metastatic breast cancer Metastatic/Recurrent Microscopy Modality Modification Monitor Monoclonal Antibodies Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Normal tissue morphology Patient Selection Patients Pattern Pertuzumab Positron-Emission Tomography Pre-Clinical Model Primary Lesion Primary Neoplasm Property Radiolabeled Reaction Recurrence Recurrent disease Refractory Refractory Disease Research Resistance Risk Role Site Solubility System Testing Therapeutic Therapeutic Monoclonal Antibodies Time Toxic effect Tracer Trastuzumab Treatment Efficacy Treatment outcome Woman Xenograft procedure base cancer cell cancer therapy chemotherapy crosslink cytotoxic cytotoxicity disease phenotype dosimetry drug distribution humanized antibody image guided image guided therapy improved outcome in vivo malignant breast neoplasm nanocarrier novel novel therapeutics outcome forecast receptor response single photon emission computed tomography standard care systemic toxicity targeted treatment therapeutic target tumor

项目摘要

Project Summary Despite significant advances in breast cancer detection and therapy, up to 30% of women diagnosed with early-stage disease are at risk of recurrence and death. Adjuvant endocrine and chemotherapy, and HER2- targeted therapy with trastuzumab monoclonal antibody, which is a standard treatment for patients with HER2- positive disease (~20% of all cases), significantly improve the outcome. Unfortunately, approximately half of HER2-positive patients do not benefit from trastuzumab or have disease that becomes refractory to it. Chemotherapy alone is of little benefit in this setting, and novel treatments that can overcome trastuzumab resistance are being developed. The trastuzumab-mertansine antibody-drug conjugate (ADC), T-DM1 (Genentech), demonstrates high efficacy in trastuzumab-refractory disease. However, the selection of patients for T-DM1 therapy is currently based on the assessment of HER2 lesion(s) status by biopsy, which may not provide reliable results for heterogeneous disease. In addition, the long circulation half-time of cytotoxic ADC can result in systemic toxicity. In this application, we propose to develop and validate an image-guided, two- component therapeutic system for targeted treatment of HER2-positive breast cancer that takes advantage of bioorthogonal in vivo click chemistry and can address the concerns related to ADC-based therapy. The central hypothesis is that an image-guided delivery system, based on the pretargeting of HER2 receptors with a bispecific antibody and cytotoxic nanocarriers, will provide real-time, noninvasive assessment and phenotyping of the disease, as well as high efficacy and reduced systemic toxicity for the treatment of trastuzumab-resistant HER2+ breast cancers. The main advantages are: (i) efficient labeling of cancer cells with a non-toxic pretargeting antibody component; (ii) high affinity binding and rapid internalization of the therapeutic cytotoxic component by pre-labeled cancer cells; (iii) a short circulation time and rapid clearance of the therapeutic component ensures low systemic toxicity; and (iv) image guidance enables selection of tumors/patients for therapy, verification of pre-labeling efficiency, and optimization of the administration time for the therapeutic component. Our preliminary studies with HER2+ breast cancer models demonstrated high efficacy and low toxicity of the pretargeting therapy, with complete remission achieved in several animals. The radiolabeled delivery components will be synthesized, characterized, and tested in preclinical models of HER2+ breast cancer in immunodefficient and immunocompetent animals. The treatment efficacy and toxicity of the pretargeting therapy will be compared to the gold standard, T-DM1. We envision that the pretargeting image-guided therapy will provide high efficacy combined with minimal toxicity. Humanized antibody, human protein carriers, bioorthogonal click chemistry, and clinical modalities used for image-guidance will ensure a translational path for the system with a future potential use in patients with recurrent metastatic breast cancer, using image-guidance to noninvasively assess HER2 expression and targeting in heterogeneous disease.

项目概要尽管乳腺癌检测和治疗取得了重大进展，但高达 30% 的女性被诊断患有乳腺癌早期疾病有复发和死亡的风险。辅助内分泌和化疗，以及 HER2- 曲妥珠单抗单克隆抗体靶向治疗，这是 HER2- 患者的标准治疗阳性疾病（约占所有病例的 20%），显着改善结果。不幸的是，大约一半 HER2 阳性患者不会从曲妥珠单抗中获益，或者患有对其难以治疗的疾病。在这种情况下，单独化疗几乎没有什么好处，而可以克服曲妥珠单抗的新疗法抵抗力正在发展。曲妥珠单抗-mertansine 抗体药物偶联物 (ADC)，T-DM1 （基因泰克），证明对曲妥珠单抗难治性疾病具有高效能。但患者的选择 T-DM1 治疗目前基于活检对 HER2 病变状态的评估，这可能不会为异质性疾病提供可靠的结果。此外，细胞毒性ADC的循环半衰期较长可导致全身毒性。在此应用中，我们建议开发并验证图像引导的双用于靶向治疗 HER2 阳性乳腺癌的成分治疗系统，该系统利用了生物正交体内点击化学，可以解决与基于 ADC 的治疗相关的问题。中心假设是基于 HER2 受体预靶向的图像引导递送系统具有双特异性抗体和细胞毒性纳米载体，将提供实时、非侵入性评估和该疾病的表型分析，以及治疗的高效性和降低的全身毒性曲妥珠单抗耐药的 HER2+ 乳腺癌。主要优点是：（i）有效标记癌细胞具有无毒的预靶向抗体成分； (ii) 高亲和力结合和快速内化预先标记的癌细胞的治疗性细胞毒性成分；（三）流通时间短、通关快治疗成分确保低全身毒性； (iv) 图像引导可以选择肿瘤/患者的治疗、预标记效率的验证以及给药时间的优化治疗成分。我们对 HER2+ 乳腺癌模型的初步研究表明，预靶向疗法的功效和低毒性，在一些动物中实现了完全缓解。放射性标记的递送成分将在临床前模型中进行合成、表征和测试免疫缺陷和免疫功能正常的动物中的 HER2+ 乳腺癌。治疗效果及毒性预靶向治疗的效果将与金标准 T-DM1 进行比较。我们预计预定目标图像引导治疗将提供高效且毒性最小的效果。人源化抗体，人蛋白质载体、生物正交点击化学和用于图像引导的临床模式将确保该系统的转化路径未来可能用于复发性转移性乳腺癌患者，使用图像引导非侵入性评估异质性疾病中的 HER2 表达和靶向。