EphA2 Immunoconjugate as Molecularly Targeted Chemotherapy for Ovarian Carcinoma
EphA2 Immunoconjugate as Molecularly Targeted Chemotherapy for Ovarian Carcinoma
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DOI：
10.1093/jnci/djp231
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发表时间：
2009-09-02
影响因子：
10.3
通讯作者：
Sood, Anil K.
中科院分区：
文献类型：
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作者：
Lee, Jeong-Won;Han, Hee Dong;Sood, Anil K.
背景EphA 2在许多类型的人类癌症中过表达，但在正常上皮组织中不存在或以低水平表达。我们研究了含有与化疗剂连接的抗EphA 2单克隆抗体（1C 1）的新型免疫缀合物是否方法在EphA 2阳性的HeyA 8和EphA 2阳性的HeyA 8细胞中检测1C 1-mcMMAF的特异性，并在EphA 2阳性的HeyA 8和EphA 2阳性的HeyA 8细胞中检测1C 1-mcMMAF的特异性。阴性SKMel 28卵巢癌细胞通过抗体结合和内化测定。对照为磷酸盐缓冲盐水（PBS）、1C 1或对照IgG-mcMMAF。在卵巢癌细胞系和肿瘤模型（每组10只小鼠）中研究存活力和凋亡。在卵巢癌的HeyA 8-luc和SKOV 3 ip 1原位小鼠模型中测试抗肿瘤活性。采用免疫组化和抗CD 31抗体鉴定内皮细胞。结果1C 1-mcMMAF免疫缀合物特异性结合EphA 2阳性的HeyA 8细胞，但不结合EphA 2阴性的细胞，并被HeyA 8细胞内化。用1C 1-mcMMAF处理以EphA 2特异性方式降低HeyA 8-luc细胞的活力。在原位小鼠模型中，与对照小鼠相比，1C 1-mcMMAF处理可抑制85%-98%的肿瘤生长（例如，对于HeyA 8肿瘤重量，1C 1-mcMMAF = 0.05 g，对照= 1.03 g;差异= 0.98 g，95%置信区间[CI] = 0.40 - 1.58 g; P = 0.001）。即使在含有HeyA 8-luc细胞的体积较大的疾病模型中，与对照治疗相比，1C 1-mcMMAF治疗也导致已建立的肿瘤消退并增加小鼠的存活率（例如，1C 1-mcMMAF vs对照，平均值= 60.6天vs 29.4天;差异= 31.2天，95% CI = 27.6至31.2天; P = 0.001）。例如，在SKOV 3 ip 1肿瘤中，1C 1-mcMMAF治疗的抗肿瘤作用与增殖减少在统计学上显著相关（例如，1C 1-mcMMAF vs对照，平均值= 44.1% vs 55.8%增殖细胞;差异= 11.7%，95% CI = 2.45%至20.9%; P = 0.01）和肿瘤细胞凋亡增加（例如，1C 1-mcMMAF vs对照，平均值= 8.6% vs 0.9%凋亡细胞;差异= 7.7%，95% CI = 3.8%至11.7%; P < .001）和小鼠内皮细胞（例如，1C 1-mcMMAF与对照组相比，平均2.8% vs 0.4%凋亡内皮细胞;差异= 2.4%，95% CI = 1.4%至4.6%;结论1C 1-mcMMAF免疫偶联物在卵巢癌临床前模型中具有抗肿瘤活性。
Background EphA2 is overexpressed in many types of human cancer but is absent or expressed at low levels in normal epithelial tissues. We investigated whether a novel immunoconjugate containing an anti-EphA2 monoclonal antibody (1C1) linked to a chemotherapeutic agent (monomethyl auristatin phenylalanine [MMAF]) through a noncleavable linker maleimidocaproyl (mc) had antitumor activity against ovarian cancer cell lines and tumor models.Methods Specificity of 1C1-mcMMAF was examined in EphA2-positive HeyA8 and EphA2-negative SKMel28 ovarian cancer cells by antibody binding and internalization assays. Controls were phosphate-buffered saline (PBS), 1C1, or control IgG-mcMMAF. Viability and apoptosis were investigated in ovarian cancer cell lines and tumor models (10 mice per group). Antitumor activities were tested in the HeyA8-luc and SKOV3ip1 orthotopic mouse models of ovarian cancer. Endothelial cells were identified by use of immunohistochemistry and anti-CD31 antibodies. All statistical tests were two-sided.Results The 1C1-mcMMAF immunoconjugate specifically bound to EphA2-positive HeyA8 cells but not to EphA2-negative cells and was internalized by HeyA8 cells. Treatment with 1C1-mcMMAF decreased the viability of HeyA8-luc cells in an EphA2-specific manner. In orthotopic mouse models, treatment with 1C1-mcMMAF inhibited tumor growth by 85%-98% compared with that in control mice (eg, for weight of HeyA8 tumors, 1C1-mcMMAF = 0.05 g and control = 1.03 g; difference = 0.98 g, 95% confidence interval [CI] = 0.40 to 1.58 g; P = .001). Even in bulkier disease models with HeyA8-luc cells, 1C1-mcMMAF treatment, compared with control treatment, caused regression of established tumors and increased survival of the mice (eg, 1C1-mcMMAF vs control, mean = 60.6 days vs 29.4 days; difference = 31.2 days, 95% CI = 27.6 to 31.2 days; P = .001). The antitumor effects of 1C1-mcMMAF therapy, in SKOV3ip1 tumors, for example, were statistically significantly related to decreased proliferation (eg, 1C1-mcMMAF vs control, mean = 44.1% vs 55.8% proliferating cells; difference = 11.7%, 95% CI = 2.45% to 20.9%; P = .01) and increased apoptosis of tumor cells (eg, 1C1-mcMMAF vs control, mean = 8.6% vs 0.9% apoptotic cells; difference = 7.7%, 95% CI = 3.8% to 11.7%; P < .001) and of mouse endothelial cells (eg, 1C1-mcMMAF vs control, mean 2.8% vs 0.4% apoptotic endothelial cells; difference = 2.4%, 95% CI = 1.4% to 4.6%; P = .034).Conclusion The 1C1-mcMMAF immunoconjugate had antitumor activity in preclinical models of ovarian carcinoma.