Engineering a multispecific receptor antagonist to inhibit cancer metastasis

已发现尿激酶型纤溶酶原激活物受体(UPAR)在血管内皮细胞过度表达。 在几乎每一种测试的癌症类型中，癌细胞及其相关的新生血管的表面， 包括原发癌、转移癌和化疗耐药癌。UPAR是一个重要的主调节器， 促进细胞外基质的降解和血管生成，以及癌细胞的增殖、黏附和 迁移。这些过程反过来又允许肿瘤快速生长和转移到体内其他部位。临床 研究表明，uPAR及其可溶性配体uPA的过度表达是低发病率的独立预测因子。 以及总体存活率。因此，uPAR是一个极具吸引力的治疗干预靶点；然而， 缺乏FDA批准的抑制UPAR的药物突显出迫切需要新的方法来治疗 有效地阻断这种受体的活性。我们将应用我们在分子和细胞生物学方面的专业知识， 生物化学和蛋白质工程开发一种新的一流生物能够有效地阻断 UPAR介导的肿瘤生长、转移和肿瘤相关血管生成。众多UPAR拮抗剂 在过去的二十年里已经发展起来，包括小分子、肽、蛋白质配体和 抗体。然而，由于它们的亲和力相对较低，这些抑制剂的有效性受到了限制。 天然的uPAR配体，和/或它们无法有效地阻止uPAR的功能，从而推动癌症的生长和 转移。蛋白质工程与多特异性靶点结合将产生uPAR抑制剂。 与以前开发的拮抗剂相比，具有更高数量级的结合亲和力。由此产生的 生物制品具有令人振奋的潜力，可以克服阻碍成功发展的关键障碍 UPAR靶向治疗，这将是侵袭性疾病靶向治疗的潜在突破 癌症。

The urokinase-type plasminogen activator receptor (uPAR) has been found to be overexpressed on the surface of cancer cells, as well as their associated neovasculature, in virtually every cancer type tested, including primary, metastatic, and chemotherapy-resistant cancers. uPAR is an important master regulator that drives extracellular matrix degradation and angiogenesis, and cancer cell proliferation, adhesion, and migration. These processes in turn allow rapid tumor growth and metastasis to other sites in the body. Clinical studies indicate overexpression of uPAR and its soluble ligand uPA are independent predictors of low diseasefree and overall survival. Thus, uPAR is an extremely attractive target for therapeutic intervention; however, the absence of an FDA-approved drug that inhibits uPAR highlights a critical need for new approaches to effectively block the activity of this receptor. We will apply our expertise in molecular and cellular biology, biochemistry, and protein engineering to develop a novel first-in-class biologic capable of effectively blocking uPAR-mediated cancer growth, metastasis, and tumor-associated angiogenesis. Numerous uPAR antagonists have been developed over the last two decades, including small molecules, peptides, protein ligands, and antibodies. However, the efficacies of these inhibitors have been limited owing to their low affinity relative to the native uPAR ligands, and/or their inability to effectively block uPAR functions that drive cancer growth and metastasis. Protein engineering, combined with multispecific target binding, will generate in uPAR inhibitors with orders of magnitude higher binding affinity compared to previously developed antagonists. The resulting biologics have exciting potential to overcome critical barriers that have prevent development of successful uPAR-targeted therapeutics, and would represent a potential breakthrough for targeted therapy of aggressive cancers.