Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer
Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer
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DOI：
10.1016/s0149-2918(00)88288-0
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发表时间：
1999-02-01
影响因子：
3.2
通讯作者：
Goldenberg, MM
中科院分区：
文献类型：
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作者：
Goldenberg, MM
人表皮生长因子受体2蛋白(HER2)在乳腺癌中的扩增已被证明与某些患者的不良临床预后有关。曲妥珠单抗(Herceptin(R)，Genentech，Inc.，加利福尼亚州南旧金山)是一种高度纯化的重组DNA人源化免疫球蛋白G1 kappa抗体，与HER2受体的胞外区域具有高亲和力和特异性。体外和体内的临床前研究表明，曲妥珠单抗单独或与紫杉醇或卡铂联合应用显著抑制过表达HER2基因产物的乳腺肿瘤来源细胞系的生长。在乳腺癌患者的治疗剂量下，曲妥珠单抗的平均半衰期为5.8天。曲妥珠单抗血药浓度达到稳态，平均血药浓度谷值为79 mU g/m L，峰值血药浓度为123 mU g/m L。在222名患者的单臂临床研究中，先静脉注射曲妥珠单抗4 mg/kg，然后每周静脉注射2 mg/kg，总有效率为14%(完全缓解2%，部分缓解12%)。在HER2蛋白过度表达程度最高(3+)的患者中，益处最大。在另一项临床研究中，469名转移性乳腺癌患者被随机分成两组，分别使用或不使用曲妥珠单抗的紫杉醇或蒽环类药物加环磷酰胺方案。曲妥珠单抗加化疗组的总体有效率显著高于单纯化疗组。紫杉醇联合曲妥珠单抗的观察到的效果最大。在临床研究中，曲妥珠单抗最常见的不良反应是发热和寒战、疼痛、虚弱、恶心、呕吐、咳嗽、腹泻、头痛、呼吸困难、感染、鼻炎和失眠。曲妥珠单抗联合化疗可导致心脏毒性、白细胞减少、贫血、腹泻、腹痛和感染。曲妥珠单抗已被美国食品和药物管理局批准为单一药物，用于治疗HER2蛋白过度表达的转移性乳腺癌患者，并接受过一种或多种化疗方案；与紫杉醇联合使用，已被批准用于治疗此类未接受化疗的患者。
Amplification of the human epidermal growth factor receptor 2 protein (HER2) in primary breast carcinomas has been shown to correlate with poor clinical prognosis for certain patients. Trastuzumab (Herceptin(R), Genentech, Inc., South San Francisco, California) is a highly purified recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody that binds with high affinity and specificity to the extracellular domain of the HER2 receptor. In vitro and in vivo preclinical studies have shown that administration of trastuzumab alone or in combination with paclitaxel or carboplatin significantly inhibits the growth of breast tumor-derived cell lines that overexpress the HER2 gene product. At therapeutic doses in breast cancer patients, the mean half-life of trastuzumab is 5.8 days. Trastuzumab serum concentrations reach steady state with mean trough and peak concentrations of 79 mu g/mL and 123 mu g/mL, respectively. In a 222-patient, single arm clinical study, treatment with a loading dose of trastuzumab 4 mg/kg administered IV followed by weekly IV doses of 2 mg/kg produced an overall response rate of 14% (2% complete remission and 12% partial remission). The beneficial effects were greatest in patients with the greatest degree (3+) of HER2 protein overexpression. In another clinical study, 469 women with metastatic breast carcinoma were randomized to a paclitaxel or anthracycline-plus-cyclophosphamide regimen with or without trastuzumab. The overall response rate was significantly greater in the trastuzumab-plus-chemotherapy group than in the chemotherapy-alone cohort. The magnitude of observed effects was greatest with paclitaxel plus trastuzumab. The most common adverse effects attributed to trastuzumab in clinical studies were fever and chills, pain, asthenia, nausea, vomiting, increased cough, diarrhea, headache, dyspnea, infection, rhinitis, and insomnia. Trastuzumab in combination with chemotherapy can lead to cardiotoxicity, leukopenia, anemia, diarrhea, abdominal pain, and infection. Trastuzumab has been approved by the US Food and Drug Administration as a single agent for the treatment of patients who have metastatic breast cancer involving overexpression of the HER2 protein and who have received 1 or more chemotherapy regimens; in combination with paclitaxel, it has been approved for the treatment of such patients who have not received chemotherapy.