Kiewlich David, Zhang Jianhuan, Gross Cynthia, Xia Wei, Larsen Brent, Cobb Ronald R, Biroc Sandra, Gu Jian-Ming, Sato Takashi, Light David R, Heitner Tara, Willuda Joerg, Vogel David, Monteclaro Felipe, Citkowicz Andrzej, Roffler Steve R, Zajchowski Deborah A
Corporate Research Oncology, Berlex Biosciences, Richmond, CA 94804, USA.
Neoplasia. 2006 Jan;8(1):18-30. doi: 10.1593/neo.05544.
The EphA2 receptor tyrosine kinase has been shown to be over-expressed in cancer and a monoclonal antibody (mAb) that activates and down-modulates EphA2 was reported to inhibit the growth of human breast and lung tumor xenografts in nude mice. Reduction of EphA2 levels by treatment with anti-EphA2 siRNA also inhibited tumor growth, suggesting that the anti-tumor effects of these agents are mediated by decreasing the levels of EphA2. As these studies employed human tumor xenograft models in nude mice with reagents whose cross reactivity with murine EphA2 is unknown, we generated a mAb (Ab20) that preferentially binds, activates, and induces the degradation of murine EphA2. Treatment of established murine CT26 colorectal tumors with Ab20 reduced EphA2 protein levels to approximately 12% of control tumor levels, yet had no effect on tumor growth. CT26 tumor cell colonization of the lung was also not affected by Ab20 administration despite having barely detectable levels of EphA2. We also generated and tested a potent agonistic mAb against human EphA2 (1G9-H7). No inhibition of humanMDA-231 breast tumor xenograft growth was observed despite evidence for >85% reduction of EphA2 protein levels in the tumors. These results suggest that molecular characteristics of the tumors in addition to EphA2 over-expression may be important for predicting responsiveness to EphA2-directed therapies.
EphA2受体酪氨酸激酶已被证明在癌症中过度表达，据报道，一种激活并下调EphA2的单克隆抗体（mAb）可抑制裸鼠体内人乳腺和肺癌异种移植瘤的生长。用抗EphA2 siRNA处理降低EphA2水平也能抑制肿瘤生长，这表明这些药物的抗肿瘤作用是通过降低EphA2水平来介导的。由于这些研究在裸鼠中使用人肿瘤异种移植模型，且所用试剂与鼠EphA2的交叉反应性未知，我们制备了一种单克隆抗体（Ab20），它能优先结合、激活并诱导鼠EphA2的降解。用Ab20处理已建立的鼠CT26结直肠癌肿瘤，可使EphA2蛋白水平降至对照肿瘤水平的约12%，但对肿瘤生长没有影响。尽管EphA2水平几乎检测不到，但给予Ab20对CT26肿瘤细胞在肺部的定植也没有影响。我们还制备并测试了一种针对人EphA2的强效激动性单克隆抗体（1G9-H7）。尽管有证据表明肿瘤中EphA2蛋白水平降低了85%以上，但未观察到对人MDA-231乳腺肿瘤异种移植生长的抑制作用。这些结果表明，除了EphA2过度表达外，肿瘤的分子特征对于预测对EphA2导向治疗的反应性可能也很重要。
