Agus David B, Gordon Michael S, Taylor Charles, Natale Ronald B, Karlan Beth, Mendelson David S, Press Michael F, Allison David E, Sliwkowski Mark X, Lieberman Gracie, Kelsey Stephen M, Fyfe Gwen
Cedars-Sinai Prostate Cancer Center and Medical Center, Los Angeles, CA 90048, USA.
J Clin Oncol. 2005 Apr 10;23(11):2534-43. doi: 10.1200/JCO.2005.03.184. Epub 2005 Feb 7.
Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy.
Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks.
Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients.
These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.
帕妥珠单抗是一种重组人源化单克隆抗体（2C4），可与HER-2受体的细胞外结构域II结合，阻断其与其他HER受体二聚化的能力。帕妥珠单抗代表了一类新型的靶向治疗药物，即HER二聚化抑制剂。开展了一项临床研究，以调查帕妥珠单抗的安全性和药代动力学，并对HER二聚化抑制作为一种治疗策略进行初步评估。
招募在标准治疗期间或之后病情进展的无法治愈的局部晚期、复发性或转移性实体瘤患者，参加帕妥珠单抗（0.5至15mg/kg）每3周静脉注射一次的剂量递增研究。
21例患者接受了帕妥珠单抗治疗，19例完成了至少两个周期。帕妥珠单抗耐受性良好。总体而言，共报告了365例不良事件，其中122例被认为可能与药物有关。其中，116例为1至2级强度。帕妥珠单抗的药代动力学与其他人性化免疫球蛋白G抗体相似，支持每3周给药一次的方案。剂量大于5mg/kg时，谷血浆浓度超过目标浓度。两名患者，一名卵巢癌患者（5.0mg/kg）和一名胰岛细胞癌患者（15.0mg/kg），实现了部分缓解。在帕妥珠单抗治疗1.5个月和6个月后，根据实体瘤疗效评价标准记录到缓解情况，分别持续了11个月和10个月。6例患者观察到疾病稳定持续超过2.5个月（范围为2.6至5.5个月）。
这些结果表明帕妥珠单抗耐受性良好，具有支持每3周给药一次的药代动力学特征，且具有临床活性，提示二聚化抑制可能是一种有效的抗癌策略。
