Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer.
Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer.
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DOI：
10.1158/0008-5472.can-11-2009
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发表时间：
2011-11-15
期刊：
影响因子：
11.2
通讯作者：
Lieber A
中科院分区：
文献类型：
--
作者：
Beyer I;van Rensburg R;Strauss R;Li Z;Wang H;Persson J;Yumul R;Feng Q;Song H;Bartek J;Fender P;Lieber A
用于治疗实体瘤的单克隆抗体（mAb）的功效受到将上皮肿瘤细胞彼此紧密连接的细胞间连接的限制。在这项研究中，我们定义了一个小的，重组腺病毒血清型3衍生的蛋白，称为连接开放器1（JO-1），它结合上皮连接蛋白桥粒芯糖蛋白2（DSG 2）。在采用Her 2/neu和EGFR阳性人癌细胞系的小鼠异种移植模型中，JO-1介导DSG 2二聚体的裂解并激活细胞内信号传导途径，从而降低紧密连接中的E-钙粘蛋白表达。值得注意的是，JO-1触发的变化使得抗Her 2/neu mAb曲妥珠单抗（赫赛汀）的肿瘤内渗透增加，并改善了对其靶受体Her 2/neu的接近，Her 2/neu部分被困在紧密连接中。这种效应直接转化为曲妥珠单抗在使用Her 2/neu阳性乳腺癌、胃癌和卵巢癌细胞的小鼠异种移植模型中的治疗疗效增加。此外，将JO-1与EGFR靶向mAb西妥昔单抗（爱必妥）组合大大改善了EGFR阳性肺癌转移模型的治疗结果。综上所述，我们的发现提供了在联合治疗中使用JO-1的临床前概念证明，该联合治疗通过产生可引起肿瘤根除的肿瘤基质蛋白的瞬时降解来增强曲妥珠单抗治疗的功效。
The efficacy of monoclonal antibodies (mAbs) used to treat solid tumors is limited by intercellular junctions which tightly link epithelial tumor cells to each another. In this study, we define a small, recombinant adenovirus serotype 3-derived protein, termed junction opener 1 (JO-1), which binds to the epithelial junction protein desmoglein 2 (DSG2). In mouse xenograft models employing Her2/neu- and EGFR-positive human cancer cell lines, JO-1 mediated cleavage of DSG2 dimers and activated intracellular signaling pathways which reduced E-cadherin expression in tight junctions. Notably, JO-1-triggered changes allowed for increased intratumoral penetration of the anti-Her2/neu mAb trastuzumab (Herceptin) as well as improved access to its target receptor, Her2/neu, which is partly trapped in tight junctions. This effect translated directly into increased therapeutic efficacy of trastuzumab in mouse xenograft models using breast, gastric, and ovarian cancer cells that were Her2/neu-positive. Furthermore, combining JO-1 with the EGFR-targeting mAb cetuximab (Erbitux) greatly improved therapeutic outcomes in a metastatic model of EGFR-positive lung cancer. Taken together, our findings offer preclinical proof of concept to employ JO-1 in combination treatments which enhance the efficacy of trastuzumab treatment, by generating a transient degradation of tumor stroma proteins that can elicit eradication of tumors.