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

 描述(由申请人提供)：我们建议开发一种基于新的治疗性单抗(MAb)的新方法来治疗浸润性和转移性癌症。靶标是细胞表面蛋白酶ADAM10和ADAM17，它们是肿瘤生长、侵袭、耐药和转移的关键驱动因素。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，以及那些潜在的铂类和紫杉烷类化疗耐药，以及靶向抗EGFR和抗血管生成治疗。虽然ADAMS是经过充分验证的抗肿瘤靶点，但由于缺乏特异性和有效性，针对其催化活性部位的抑制剂未能通过临床试验。同样，临床上追求的下游靶点的抑制剂，如-分泌酶， 由于对非肿瘤细胞的副作用而遭受类似的限制。我们已经确定了一种新的干预策略，该策略基于针对活性必需的非催化底物识别ADAM10口袋的单抗。这种单抗选择性地识别肿瘤中过多的活性ADAM10群体，并抑制致癌信号和肿瘤生长，但在动物身上没有显示出剂量限制性毒性。与其他方法相比，我们的方法提供了三大优势：i)它同时针对多个致癌途径，因此患者产生抗药性的可能性要低得多；ii)与化疗和其他方法不同，它不仅针对快速分裂的肿瘤细胞，而且针对不会侵袭性分裂的肿瘤干细胞；iii)它选择性地以肿瘤特异性构象为靶点，使其成为肿瘤生长和转移所必需的蛋白质的靶点，从而不影响非肿瘤细胞。在R21的应用中，我们建议研究抗体的分子作用机制，进一步鉴定其治疗潜力，并产生和鉴定针对ADAM17底物结合结构域的单抗。尽管这项研究存在相当大的风险，但其结果可能为侵袭性和转移性癌症的治疗提供一种高效和新颖的干预方法。

 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.