Antitumor Effects and Normal-Tissue Toxicity of 111In-Nuclear Localization Sequence-Trastuzumab in Athymic Mice Bearing HER-Positive Human Breast Cancer Xenografts
Antitumor Effects and Normal-Tissue Toxicity of 111In-Nuclear Localization Sequence-Trastuzumab in Athymic Mice Bearing HER-Positive Human Breast Cancer Xenografts
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DOI：
10.2967/jnumed.109.072389
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发表时间：
2010-07-01
影响因子：
9.3
通讯作者：
Reilly, Raymond M.
中科院分区：
文献类型：
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作者：
Costantini, Danny L.;McLarty, Kristin;Reilly, Raymond M.
核内定位序列-曲妥珠单抗是一种放射免疫治疗剂，由NLS修饰的曲妥珠单抗(CGYGPKKKRKVGG)组成，用俄歇电子发射体In-111标记。我们的目的是评价In-111-NLS-曲妥珠单抗在小鼠体内的肿瘤生长抑制特性和正常组织毒性。方法：比较In-111-NLS-曲妥珠单抗在BALB/c小鼠体内的药代动力学。给BALB/c小鼠腹腔注射3.7~18.5MBq(4 mg/kg)的In-111-NLS-曲妥珠单抗2wk后，通过监测体重、组织病理学检查和血液学(白细胞、血小板、红细胞和血红蛋白)或临床生化(丙氨酸转氨酶和肌酐)参数来确定正常组织毒性。定义了不可观察的不良反应水平(NOAEL)剂量。荷人乳腺癌MDA-MB-361和MDA-MB-231裸鼠皮下移植瘤(分别为5.0×10(5)和0.5×10(5)HER2/细胞)，用NOAEL单剂或2剂腹腔注射，间隔2wk。对照组给予In-111-曲妥珠单抗、曲妥珠单抗、非特异性In-111-NLS-人免疫球蛋白(HIGG)或生理盐水。结果：In-111-NLS-曲妥珠单抗的生物利用度为0.7。NOAEL剂量为9.25MBq(4 mg/kg)；大于或等于18.5MBq的剂量会降低白细胞或血小板计数，27.7MBq的剂量会降低红细胞计数。在测试的任何剂量下，丙氨酸转氨酶或肌酐都没有增加。肝脏、肾脏、心脏或脾没有形态变化，也没有体重减轻。与接受In-111-曲妥珠单抗、曲妥珠单抗、In-111-NLS-HIGG或生理盐水的小鼠相比，单剂量In-111-NLS-曲妥珠单抗(9.25MBq)在60d后显著减缓了肿瘤的生长速度(分别为0.014 d(1)比0.033 d(1)、0.046 d(1)、0.030 d(1)和0.061 d(1)；P<0.05)。In-111-NLS-曲妥珠单抗对MDA-MB-231肿瘤生长无明显影响。与曲妥珠单抗或生理盐水组相比，间隔2wk的两个剂量的In-111-NLS-曲妥珠单抗(9.25MBq；4 mg/kg)可提高携带MDA-MB-361肿瘤的小鼠的存活率。140d分别为96d和84d；P分别为0.001和0.027)。结论：In-111-NLS-曲妥珠单抗是一种有希望的放射免疫治疗药物，可有效治疗HER2高表达乳腺癌。
In-111-nuclear localization sequence-trastuzumab is a radioimmunotherapeutic agent consisting of trastuzumab modified with NLS peptides (CGYGPKKKRKVGG) and labeled with the Auger electron emitter In-111. Our objectives were to evaluate the tumor growth-inhibitory properties and normal-tissue toxicity of In-111-NLS-trastuzumab in mice after intraperitoneal administration. Methods: The pharmacokinetics of In-111-NLS-trastuzumab after intravenous (tail vein) or intraperitoneal injection in BALB/c mice were compared. Normal-tissue toxicity was determined in BALB/c mice at 2 wk after intraperitoneal injection of 3.7-18.5 MBq (4 mg/kg) of In-111-NLS-trastuzumab by monitoring body weight, histopathologic examination of tissues, and hematology (white blood cell, platelet, red blood cell, and hemoglobin) or clinical biochemistry (alanine transaminase and creatinine) parameters. A no-observable-adverse-effect-level (NOAEL) dose was defined. Athymic mice bearing subcutaneous MDA-MB-361 or MDA-MB-231 human breast cancer xenografts (5.0 x 10(5) or 0.5 x 10(5) HER2/cell, respectively) were treated with a single NOAEL dose or 2 doses administered intraperitoneally and separated by 2 wk. Control groups were administered In-111-trastuzumab, trastuzumab, nonspecific In-111-NLS-human IgG (hIgG), or normal saline. Results: The bioavailability of In-111-NLS-trastuzumab after intraperitoneal injection was 0.7. The NOAEL dose was 9.25 MBq (4 mg/kg); doses greater than or equal to 18.5 MBq decreased white blood cell or platelet counts, and doses of 27.7 MBq decreased red blood cell counts. There was no increase in alanine transaminase or creatinine at any doses tested. There were no morphologic changes to the liver, kidneys, heart, or spleen or loss of body weight. A single dose of In-111-NLS-trastuzumab (9.25 MBq)-compared with mice receiving In-111-trastuzumab, trastuzumab, In-111-NLS-hIgG, or normal saline-significantly slowed the rate of growth of MDA-MB-361 tumors over 60 d (0.014 d (1) vs. 0.033 d (1), 0.046 d (1), 0.030 d (1), and 0.061 d (1), respectively; P, 0.05). In-111-NLS-trastuzumab had no effect on the growth of MDA-MB-231 tumors. Two doses of In-111-NLS-trastuzumab (9.25 MBq; 4 mg/ kg) separated by 2 wk increased the survival of mice with MDA-MB-361 tumors, compared with mice treated with trastuzumab or normal saline (. 140 d vs. 96 and 84 d, respectively; P, 0.001 or 0.027, respectively). Conclusion: In-111-NLS-trastuzumab is a promising radioimmunotherapeutic agent that could be effective for treatment of HER2-overexpressing breast cancer in humans.