Lund Ida K, Rasch Morten G, Ingvarsen Signe, Pass Jesper, Madsen Daniel H, Engelholm Lars H, Behrendt Niels, Høyer-Hansen Gunilla
The Finsen Laboratory, Copenhagen University Hospital Copenhagen, Denmark.
Front Pharmacol. 2012 Jun 28;3:122. doi: 10.3389/fphar.2012.00122. eCollection 2012.
Identification of targets for cancer therapy requires the understanding of the in vivo roles of proteins, which can be derived from studies using gene-targeted mice. An alternative strategy is the administration of inhibitory monoclonal antibodies (mAbs), causing acute disruption of the target protein function(s). This approach has the advantage of being a model for therapeutic targeting. mAbs for use in mouse models can be obtained through immunization of gene-deficient mice with the autologous protein. Such mAbs react with both species-specific epitopes and epitopes conserved between species. mAbs against proteins involved in extracellular proteolysis, including plasminogen activators urokinase plasminogen activator (uPA), tissue-type plasminogen activator (tPA), their inhibitor PAI-1, the uPA receptor (uPAR), two matrix metalloproteinases (MMP9 and MMP14), as well as the collagen internalization receptor uPARAP, have been developed. The inhibitory mAbs against uPA and uPAR block plasminogen activation and thereby hepatic fibrinolysis in vivo. Wound healing, another plasmin-dependent process, is delayed by an inhibitory mAb against uPA in the adult mouse. Thromboembolism can be inhibited by anti-PAI-1 mAbs in vivo. In conclusion, function-blocking mAbs are well-suited for targeted therapy in mouse models of different diseases, including cancer.
确定癌症治疗靶点需要了解蛋白质在体内的作用，这可以通过对基因敲除小鼠的研究获得。另一种策略是给予抑制性单克隆抗体（mAb），从而急性破坏靶蛋白的功能。这种方法具有作为治疗靶点模型的优势。用于小鼠模型的mAb可通过用自体蛋白免疫基因缺陷小鼠获得。此类mAb可与物种特异性表位以及物种间保守的表位发生反应。已经开发出针对参与细胞外蛋白水解的蛋白质的mAb，包括纤溶酶原激活剂尿激酶型纤溶酶原激活剂（uPA）、组织型纤溶酶原激活剂（tPA）、它们的抑制剂PAI-1、uPA受体（uPAR）、两种基质金属蛋白酶（MMP9和MMP14），以及胶原内化受体uPARAP。针对uPA和uPAR的抑制性mAb可阻断纤溶酶原激活，从而在体内抑制肝脏纤维蛋白溶解。伤口愈合是另一个纤溶酶依赖性过程，在成年小鼠中，针对uPA的抑制性mAb会延迟伤口愈合。体内抗PAI-1 mAb可抑制血栓栓塞。总之，功能阻断性mAb非常适合在包括癌症在内的不同疾病的小鼠模型中进行靶向治疗。
