Gerspach Jeannette, Németh Julia, Münkel Sabine, Wajant Harald, Pfizenmaier Klaus
Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart, 70569, Germany.
Cancer Immunol Immunother. 2006 Dec;55(12):1590-600. doi: 10.1007/s00262-006-0162-6. Epub 2006 Apr 25.
We have previously developed TNF prodrugs comprised of a N-terminal scFv targeting, a TNF effector and a C-terminal TNFR1-derived inhibitor module linked to TNF via a MMP-2 motif containing peptide, allowing activation by MMP-2-expressing tumor cells. To overcome the known heterogeneity of matrix metalloprotease expression, we developed TNF prodrugs that become processed by other tumor and/or stroma-associated proteases. These TNF prodrugs comprise either an uPA-selective or a dual uPA-MMP-2-specific linker which displayed efficient, target-dependent and cleavage sequence-specific activation by the corresponding tumor cell-expressed proteases. Selective pharmacologic inhibition of endogenous uPA and MMP-2 confirm independent prodrug processing by these two model proteases and indicate the functional superiority of a prodrug containing a multi-specific protease linker. Processing optimised TNF prodrugs should increase the proportion of active therapeutic within the targeted tissue and thus potentially enhance tumor response rate.
我们之前开发了肿瘤坏死因子（TNF）前药，其由一个靶向N端的单链抗体片段（scFv）、一个TNF效应器以及一个通过含基质金属蛋白酶-2（MMP-2）基序的肽与TNF相连的C端肿瘤坏死因子受体1（TNFR1）衍生抑制剂模块组成，可被表达MMP-2的肿瘤细胞激活。为克服已知的基质金属蛋白酶表达异质性，我们开发了可被其他肿瘤和/或基质相关蛋白酶加工的TNF前药。这些TNF前药包含一个尿激酶型纤溶酶原激活剂（uPA）选择性或uPA-MMP-2双特异性接头，其可被相应肿瘤细胞表达的蛋白酶进行高效、靶点依赖性及切割序列特异性激活。对内源性uPA和MMP-2的选择性药理抑制证实了这两种模型蛋白酶对前药的独立加工，并表明含多特异性蛋白酶接头的前药具有功能优势。经过加工优化的TNF前药应会增加靶向组织内活性治疗药物的比例，从而有可能提高肿瘤反应率。
