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：
9893831
负责人：
Dmitri Artemov
金额：
$ 39.4万
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/9893831
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 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 multiphoton microscopy 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.

项目摘要尽管在乳腺癌检测和治疗方面取得了重大进展，但多达30％的妇女被诊断出患有早期疾病有复发和死亡的风险。辅助内分泌和化学疗法以及HER2- 曲妥珠单抗单克隆抗体的靶向治疗，这是HER2-患者的标准治疗阳性疾病（所有病例的20％）显着改善了结果。不幸的是，大约一半 HER2阳性患者不会从曲妥珠单抗中受益，也不会受益于它的疾病。在这种情况下，仅化学疗法几乎没有好处，并且可以克服曲妥珠单抗的新型治疗方法正在发展抵抗。 Trastuzumab-mertansine抗体 - 药物缀合物（ADC），T-DM1 （Genentech），表现出在曲妥珠单抗 - fractractory疾病中的高疗效。但是，选择患者对于T-DM1治疗目前是基于对HER2病变状态进行活检的评估，这可能不会为异质疾病提供可靠的结果。另外，细胞毒性ADC的长时间循环半场可能导致全身毒性。在此应用中，我们建议开发和验证图像引导的两种用于针对HER2阳性乳腺癌的靶向治疗的组件治疗系统生物正交在体内点击化学，可以解决与基于ADC的治疗有关的问题。中心假设是，基于HER2受体的预测，图像引导的输送系统使用双特异性抗体和细胞毒性纳米载体，将提供实时的无创评估该疾病的表型以及高疗效和降低的全身毒性治疗抗曲妥珠单抗的HER2+乳腺癌。主要优点是：（i）有效的癌细胞标记具有无毒的有前途抗体成分；（ii）高亲和力结合和快速的内在化预先标记的癌细胞的治疗性细胞毒性成分；（iii）较短的循环时间和快速清理治疗成分可确保全身性毒性低；（iv）图像指导可以选择肿瘤/患者进行治疗，验证预先标记的效率以及优化给药时间治疗成分。我们对HER2+乳腺癌模型的初步研究表明很高有效疗法的功效和低毒性，几只动物完全缓解。放射标记的递送组件将在临床前模型合成，表征和测试 HER2+乳腺癌在免疫降解和免疫能力的动物中。治疗功效和毒性将有预期的疗法与黄金标准TM1进行比较。我们设想有预期的图像指导的疗法将提供高疗效，并结合最小的毒性。人源化抗体，人类蛋白质携带者，生物正交点击化学和用于图像引导的临床方式将确保该系统的翻译路径在复发性转移性乳腺癌患者中具有未来潜在用途，使用图像引导来非侵入性评估HER2表达和靶向异质疾病。