Function-blocking anti-ADAM protease antibodies for inhibition of tumorigenesis

用于抑制肿瘤发生的功能阻断性抗 ADAM 蛋白酶抗体

基本信息

批准号：
8881452
负责人：
DIMITAR B NIKOLOV
金额：
$ 22.96万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8881452
关键词：
Active Sites Adverse effects Affect Amphiregulin Animals Antibodies Autocrine Communication Binding Biological Models Blood Vessels Catalytic Domain Cell Line Cell Proliferation Cell physiology Cell surface Cells Clinical Clinical Trials Coculture Techniques Complex Disintegrins Disseminated Malignant Neoplasm Dose-Limiting Drug resistance EGF gene Endothelial Cells Enzymes Ephrin-A2 Ephrins Epidermal Growth Factor Receptor Epiregulin Growth Heparin Binding Heregulin Hypoxia In Vitro Intervention LIM Domain Ligands Lymphoma Lymphomagenesis Malignant Neoplasms Mediating Metalloproteases Modeling Molecular Conformation Molecular Mechanisms of Action Monoclonal Antibodies Mus Names Neoplasm Metastasis Neuregulins Nutrient Oncogenic Organ Organogenesis Outcome Pathway interactions Patients Peptide Hydrolases Platinum Play Population Production Property Proteins Reagent Regulation Research Resistance Resistance development Risk Role Signal Transduction Specificity Structure Substrate Specificity Taxane Compound Testing Therapeutic Therapeutic Monoclonal Antibodies Time Toxic effect Tumor Stem Cells Tumor Tissue Xenobiotics Xenograft Model angiogenesis base betacellulin chemotherapy in vivo in vivo Model inhibitor/antagonist insight intercellular communication jagged1 protein neoplastic cell neutralizing monoclonal antibodies notch protein novel novel strategies novel therapeutics oxygen transport paracrine public health relevance resistance mechanism secretase taxane therapeutic development tumor tumor growth tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): We propose to develop a novel approach for the treatment of invasive and metastatic cancers based on novel therapeutic monoclonal antibodies (mAb). The targets are the cell-surface proteases ADAM10 and ADAM17, which are key drivers of tumor growth, invasion, drug resistance and metastasis. ADAM10 is activated in most cancers and, in turn, activates oncogenic pathways, including EGFR/ErbB, Notch, and Eph, as well as those underlying resistance to platinum and taxane-based chemotherapies, and to targeted anti-EGFR and anti-angiogenic therapies. While ADAMs are well-validated anti-tumor targets, inhibitors against their catalytic active sites failed clinical trials due to lack of specficity and efficacy. Likewise, clinically pursued inhibitors of downstream targets, such as -secretase, suffer from similar limitations due to side effects on non-tumor cells. We have identified a novel intervention strategy based on a mAb targeting an essential for activity, non- catalytic substrate-recognition ADAM10 pocket. This mAb selectively recognizes an active ADAM10 population over-represented in tumors, and inhibits oncogenic signaling and tumor growth, but does not show dose-limiting toxicities in animals. Our approach provides three significant advantages over the alternatives: i) It targets multiple oncogenic pathways at the same time, therefore patients are much less likely to develop resistance to treatment; ii) Unlike chemotherapy and other approaches, it targets not only rapidly dividing tumor cells, but also tumor stem cells, which do not aggressively divide; iii) It selectively targets a tumor-specific conformation of an essential for tumor growth and metastasis protein, thus not affecting non-tumor cells. In this R21 application we propose to investigate the molecular mechanism of action of the antibody, to further characterize its therapeutic potential, and to generate and characterize mAbs against the substrate-binding domain of ADAM17. Although this study involves considerable risk, its outcome could provide a highly effective and novel intervention approach for the cure of invasive and metastatic cancer.

描述（由申请人提供）：我们建议开发一种基于新型治疗性单克隆抗体（mAb）的治疗侵袭性和转移性癌症的新方法，其靶标是细胞表面蛋白酶 ADAM10 和 ADAM17，它们是肿瘤的关键驱动因素。 ADAM10 在大多数癌症中被激活，进而激活致癌途径，包括 EGFR/ErbB、Notch 和Eph 以及对铂类和紫杉烷类化疗以及靶向抗 EGFR 和抗血管生成疗法的潜在耐药性。同样，临床上寻求的下游靶点抑制剂，例如γ-分泌酶，由于对非肿瘤细胞的副作用，我们已经确定了一种基于针对活性必需的非催化底物识别 ADAM10 口袋的新型干预策略，该 mAb 选择性地识别活性 ADAM10 群体。与其他方法相比，我们的方法具有三个显着优势：i) 它同时针对多种致癌途径。 ii) 与化疗和其他方法不同，它不仅靶向快速分裂的肿瘤细胞，而且靶向不积极分裂的肿瘤干细胞；iii) 它选择性地靶向肿瘤； -肿瘤生长和转移所必需的蛋白质的特异性构象，因此不影响非肿瘤细胞在该R21应用中，我们建议研究抗体的分子作用机制，以进一步表征其治疗潜力，并生成和表征。对抗底物结合的单克隆抗体尽管这项研究涉及相当大的风险，但其结果可以为治愈侵袭性和转移性癌症提供一种高效且新颖的干预方法。