Reversing Drug Resistance in Tumors with Clickable Antibody Pairs

利用可点击的抗体对逆转肿瘤的耐药性

基本信息

批准号：
10566266
负责人：
Patricia Manuela Ribeiro Pereira
金额：
$ 63.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566266
关键词：
Affinity Antibodies Antibody Binding Sites Antibody Therapy Antibody-drug conjugates Binding Biodistribution Breast Breast Cancer Cell Breast Cancer Model Cancer Etiology Cancer cell line Cell surface Classification Clinical Clinical Trials Complex Copper Cyclooctenes Data Dimerization Disease Disease Progression Dose Drug Delivery Systems Drug Kinetics Drug resistance ERBB2 gene Effectiveness Eligibility Determination Endocytosis Epitopes Foundations Future Goals Heterogeneity Human Image Imaging technology Immunohistochemistry Incidence Investigation Label Malignant Neoplasms Mammary Neoplasms Medical Membrane Methodology Molecular Monitor Mutation Oncogenic Organoids Pathway interactions Patient Care Patients Pertuzumab Pharmaceutical Preparations Pharmacotherapy Population Positron-Emission Tomography Pre-Clinical Model Predisposition Protein Overexpression Proteins Randomized Reaction Receptor Protein-Tyrosine Kinases Refractory Resistance Resistance development Safety Scheme Signal Pathway Site Stomach Stomach Neoplasms Surface Testing Therapeutic Therapeutic Studies Time Tissues Toxic effect Translations Trastuzumab Treatment Efficacy Treatment outcome Xenograft procedure cancer cell clinical translation crosslink cytotoxic dosimetry drug sensitivity effective therapy extracellular gastric cancer cell imaging study improved improved outcome malignant breast neoplasm malignant stomach neoplasm molecular imaging mortality novel novel strategies novel therapeutic intervention patient derived xenograft model permissiveness pre-clinical preclinical study prevent receptor resistance mechanism response standard of care targeted delivery therapeutically effective therapy resistant trafficking treatment response tumor tumor heterogeneity uptake

项目摘要

PROJECT SUMMARY/ABSTRACT – The incidence of gastric and breast cancers is increasing rapidly, rating fourth and fifth leading causes of cancer mortality worldwide. In patients clinically classified as HER2-positive (ERBB2 amplification and/or 2+/3+ protein overexpression by immunohistochemistry), antibody-drug conjugates (ADC) prolong progression-free and overall survival. However, these therapies have low activity in HER2-low cancer cells, and not all HER2-positive tumors benefit, or even those who initially respond inevitably develop resistance over time. Guided by preclinical data we obtained in HER2 heterogeneous patient-derived xenografts demonstrating that an increase in HER-ADC endocytosis enhances therapeutic efficacy, we developed approaches of antibody delivery that result in a 15.5-fold increase of ADC internalization in cancer cells. Our novel approach uses pertuzumab and trastuzumab-drug antibodies that click at the surface of cancer cells upon binding distinct HER2 domains to increase the number of HER2-ADC complexes and further enhance the rate of HER2-ADC endocytosis. Antibody-PET imaging studies that we have generated demonstrate that our approach increases the uptake of 89Zr-ADC in heterogeneous tumors containing HER2-high and HER2-low cancer cells. Here, we will optimize clickable pairs of two epitope-distinct antibody-ADC biomolecules to enhance tumor targeting and drug delivery in resistant models of breast and gastric cancer. In addition to test the potential of our approach in cancer cell lines and organoids, we will perform randomized imaging and therapeutic studies in patient-derived breast and gastric xenografts representing three tumor populations: ADC-eligible tumors of HER2 heterogeneity, ADC-ineligible tumors, and ADC-resistant tumors. We will determine the molecular imaging (89Zr-Antibody PET), safety, pharmacokinetic profile, and therapeutic efficacy of ADC alone (no-click) versus ADC plus pertuzumab conjugated with clicking pairs (click). These randomized preclinical studies will allow us to identify molecular features that confer drug sensitivity or resistance to this promising investigational approach. Aim 1 will optimize pertuzumab/ADC clicking pairs with improved tumor uptake and drug delivery when compared with ADC monotherapies and Aim 2 will validate the use of antibody clicking pairs as a new therapeutic approach. The two aims will provide important new preclinical data on the use of antibody clicking pairs to enhance drug delivery, which could provide an excellent foundation for many future investigations, including the clinical translation of using clicking pairs to enhance drug delivery and the potential broader application to other membrane receptors and heterogeneous tumors. The long-term translational objectives of the studies proposed are to establish a foundation for a clinical trial using antibody clicking to prevent or delay drug resistance in patients with heterogeneous breast and gastric cancers.

项目摘要/摘要——胃癌和乳腺癌的发病率正在迅速增加，评级临床分类为 HER2 阳性患者的第四和第五大癌症死亡原因。（通过免疫组织化学检测 ERBB2 扩增和/或 2+/3+ 蛋白过表达）、抗体-药物偶联物 (ADC) 延长无进展生存期和总生存期，但这些疗法在 HER2 低的情况下活性较低。癌细胞，并且并非所有 HER2 阳性肿瘤都受益，甚至那些最初有反应的肿瘤也不可避免地会发展以我们在 HER2 异质性患者来源的异种移植物中获得的临床前数据为指导。为了证明 HER-ADC 内吞作用的增加可以增强治疗效果，我们开发了抗体递送方法可导致癌细胞中 ADC 内化增加 15.5 倍。新方法使用帕妥珠单抗和曲妥珠单抗药物抗体，点击癌细胞表面结合更多不同的 HER2 结构域以增加 HER2-ADC 复合物的数量并提高速率我们进行的 HER2-ADC 内吞作用的抗体-PET 成像研究表明我们的该方法增加了含有 HER2-high 和 HER2-low 的异质肿瘤中 89Zr-ADC 的摄取在这里，我们将优化两个表位不同的抗体-ADC 生物分子的可点击对，以增强癌细胞的功能。除了测试乳腺癌和胃癌耐药模型中的肿瘤靶向和药物递送。根据我们在癌细胞系和类器官中的方法，我们将进行随机成像和治疗研究在代表三个肿瘤群体的患者来源的乳腺和胃异种移植物中：符合 ADC 资格的肿瘤 HER2 异质性、不适合 ADC 的肿瘤和 ADC 耐药的肿瘤我们将通过分子成像来确定。 (89Zr-抗体 PET)、单独 ADC（无点击）与单独 ADC 的安全性、药代动力学特征和治疗效果对比 ADC 加帕妥珠单抗与点击对 (click) 结合，这些随机临床前研究将使我们能够进行。以确定赋予药物敏感性或对这种有希望的研究方法的耐药性的分子特征。目标 1 将优化帕妥珠单抗/ADC 对，与相比，改善肿瘤摄取和药物递送 ADC 单一疗法和 Aim 2 将验证抗体点击对作为新治疗方法的使用。这两个目标将为使用抗体点击对增强药物提供重要的新临床前数据交付，这可以为许多未来的研究提供良好的基础，包括临床使用点击对增强药物输送的翻译以及在其他领域的潜在更广泛应用膜受体和异质肿瘤。提出的研究的长期转化目标。旨在为临床试验抗体奠定基础，利用点击来预防或延迟耐药性患有异质性乳腺癌和胃癌的患者。