Enhanced efficacy of radioimmunotherapy with 90Y-CHX-A"-DTPA-hu3S193 by inhibition of epidermal growth factor receptor (EGFR) signaling with EGFR tyrosine kinase inhibitor AG1478
Enhanced efficacy of radioimmunotherapy with 90Y-CHX-A"-DTPA-hu3S193 by inhibition of epidermal growth factor receptor (EGFR) signaling with EGFR tyrosine kinase inhibitor AG1478
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DOI：
10.1158/1078-0432.ccr-1004-0019
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发表时间：
2005-10-01
影响因子：
11.5
通讯作者：
Scott, AM
中科院分区：
文献类型：
--
作者：
Lee, FT;Mountain, AJ;Scott, AM
目的：表皮生长因子受体（EGFR）特异性的单克隆抗体和酪氨酸激酶抑制剂已被证明可以增强EGFR阳性肿瘤的外照射效果。EGFR酪氨酸激酶抑制剂消除EGFR信号传导对放射免疫治疗疗效的影响以前尚未报道。本研究调查了EGFR酪氨酸激酶抑制剂对人癌症异种移植模型中放射免疫治疗的功效的影响。实验设计：研究了人源化抗LewisY抗体hu 3S 193和EGFR酪氨酸激酶抑制剂AG 1478。BALB/c裸鼠移植A431鳞癌细胞。在该模型中评价Y-90-CHX-A”-DTPA-hu 3S 193的初始生物分布性质。在治疗实验中，用盐水作为安慰剂、0.4mg AG 1478 i. p.（2周内6个剂量）、单次i. v.注射未标记的hu 3S 193或90 Y-CHX-A”-DTPA-hu 3S 193（12.5、25、50或100 90）。随后在A431模型中评价0.4mg AG 1478 i. p.和25 μ Ci（Y-CHX）-Y-90-A”-DTPA-hu 3S 193 i. v.的组合。生物分布研究显示，肿瘤中的摄取极好（90.33 +/- 38.84%ID/g），在注射后24至72小时达到峰值，并具有延长的保留。Y-90-CHX-A”-DTPA-hu 3S 193在25、50和100 μ Ci剂量下显著抑制A431异种移植物生长。0.4mg AG 1478与单剂量25 μ Ci 90-Y-CHX-A”-DTPA-hu 3S 193的组合与任一单独药剂相比导致功效显著增强结论：EGFR酪氨酸激酶抑制剂AG 1478显著增强了90 Y-CHX-A”-DTPA-hu 3S 193的放射免疫治疗效果。需要进一步研究EGFR酪氨酸激酶抑制剂和放射免疫疗法治疗EGFR表达肿瘤的给药方案。
Purpose: Monoclonal antibodies and tyrosine kinase inhibitors specific for the epidermal growth factor receptor (EGFR) have been shown to enhance the effect of external beam radiation on EGFR-positive tumors. The effect of EGFR signaling abrogation by EGFR tyrosine kinase inhibitor on the efficacy of radioimmunotherapy has not been reported previously. This study investigated the effect of EGFR tyrosine kinase inhibition on the efficacy of radioimmunotherapy in a human cancer xenograft model.Experimental Design: The humanized anti - LewisYantibody hu3S193 and the EGFR tyrosine kinase inhibitor AG1478 were studied. BALB/c nude mice were engrafted with A431 squamous carcinoma cells. Initial biodistribution properties of the Y-90-CHX-A"-DTPA-hu3S193 were evaluated in this model. In therapy experiments, cohorts of four to five xenografted mice were treated with saline as placebo, 0.4 mg AG1478 i.p. (six doses over 2 weeks), single i.v.. injections of unlabeled hu3S193, or 90Y-CHX-A"-DTPA-hu3S193 (12.5, 25, 50, or 100 90). The combination of 0.4 mg AG1478 i.p. and 25 mu Ci (Y-CHX)-Y-90-A"-DTPA-hu3S193 i.v. was subsequently evaluated in the A431 model.Results: 90Y-CHX-A"-DTPA-hu3S193 retained excellent immunoreactivity after radiolabeling. The biodistribution study showed excellent uptake in tumor (90.33 +/- 38.84%ID/g) peaking at 24 to 72 hours after injection and with prolonged retention. Y-90-CHX-A"-DTPA-hu3S193 significantly inhibited A431 xenograft growth at 25, 50, and 100 mu Ci doses.The combination of 0.4 mg AG1478 with a single dose of 25 mu Ci 90Y-CHX-A"-DTPA-hu3S193 resulted in a significant enhancement of efficacy compared with either agent alone (P = 0.013).Conclusions: The efficacy of radioimmunotherapy with 90Y-CHX-A"-DTPA-hu3S193 is significantly enhanced by EGFR tyrosine kinase inhibitor AG1478. Further investigations of dosing regimens using EGFR tyrosine kinase inhibitors and radioimmunotherapy in the treatment of EGFR expressing tumors are warranted.