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

• 批准号: 9024489
• 负责人: DIMITAR B NIKOLOV
• 金额: $ 19.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9024489
• 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; 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

 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）：我们提出开发一种基于新型治疗性单克隆抗体（mAb）治疗浸润性和转移性癌症的新方法。靶点是细胞表面蛋白酶ADAM 10和ADAM 17，它们是肿瘤生长、侵袭、耐药性和转移的关键驱动因素。ADAM 10在大多数癌症中被激活，反过来又激活致癌途径，包括EGFR/ErbB、Notch和Eph，以及对铂和紫杉烷化疗以及靶向抗EGFR和抗血管生成疗法的潜在耐药性。虽然亚当斯是经过充分验证的抗肿瘤靶点，但针对其催化活性位点的抑制剂由于缺乏特异性和有效性而在临床试验中失败。同样，临床上追求的下游靶点的抑制剂，如β-分泌酶， 由于对非肿瘤细胞的副作用而受到类似的限制。我们已经确定了一种新的干预策略，该策略基于靶向活性必需的非催化底物识别ADAM 10口袋的mAb。该mAb选择性识别肿瘤中过度表达的活性ADAM 10群体，并抑制致癌信号传导和肿瘤生长，但在动物中未显示剂量限制性毒性。我们的方法提供了三个显著的优势：i）它同时靶向多个致癌途径，因此患者不太可能对治疗产生耐药性; 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，而且靶向肿瘤干细胞，这些肿瘤干细胞不会积极分裂; iii）它选择性地靶向肿瘤生长和转移必需蛋白的肿瘤特异性构象，因此不影响非肿瘤细胞。在R21申请中，我们建议研究抗体的分子作用机制，进一步表征其治疗潜力，并生成和表征针对ADAM 17底物结合结构域的mAb。虽然这项研究涉及相当大的风险，但其结果可能为浸润性和转移性癌症的治疗提供一种高效和新颖的干预方法。