de Bono Johann S, Tolcher Anthony W, Forero Andre, Vanhove Gertrude F A, Takimoto Chris, Bauer Robert J, Hammond Lisa A, Patnaik Amita, White Mark L, Shen Sui, Khazaeli Muhammad B, Rowinsky Eric K, LoBuglio Albert F
Institute For Drug Development, Cancer Therapy and Research Center, San Antonio, Texas, USA.
Clin Cancer Res. 2004 Nov 15;10(22):7555-65. doi: 10.1158/1078-0432.CCR-04-0729.
To determine the feasibility of administration, safety, toxicity, immunogenicity, pharmacokinetics, maximum tolerated dose, and biodistribution of ING-1, a high-affinity, Human-Engineered monoclonal antibody (heMAb) to the Mr 40,000 epithelial cell adhesion molecule Ep-CAM, in patients with advanced adenocarcinomas.
ING-1 was initially administered to patients as a 1-hour intravenous infusion every 3 weeks. Toxicity and pharmacokinetic data led to the evaluation of a weekly schedule. The distribution of iodine-131 (131I)-labeled ING-1 was studied.
Twenty-five patients received 82 courses of ING-1. Minimal toxicity was initially observed at the 0.03-, 0.10-, and 0.30-mg/kg dose levels. A patient dosed at 1.0 mg/kg developed acute pancreatitis with severe abdominal pain, nausea, and vomiting. A patient dosed at 0.3 mg/kg had an asymptomatic amylase and lipase elevation to 502 units/L and 1,627 units/L, respectively. Both patients made uncomplicated recoveries. No other dose-limiting toxicities were observed. Regardless of dose, the volume of distribution (mean +/- SEM) was 46.6 +/- 1.6 mL/kg. ING-1 clearance decreased with increasing dose. To minimize toxicity and increase dose intensity, we then administered ING-1 weekly. No significant toxicity was observed in 7 patients dosed at 0.1 mg/kg. Studies of 131I-labeled ING-1 biodistribution showed radiolocalization to colorectal and prostate cancers. A patient with colorectal cancer had an 80% decrement in the levels of carcinoembryonic antigen.
The recommended dose for ING-1 is 0.10 mg/kg by intravenous infusion weekly. The absence of severe toxicity at this dose, low immunogenicity, and preliminary evidence of ING-1 tumor localization and antitumor efficacy support the further clinical development of this antibody to treat Ep-CAM-positive malignant diseases.
确定高亲和力人源化单克隆抗体（heMAb）ING-1对分子量为40,000的上皮细胞粘附分子Ep-CAM的给药可行性、安全性、毒性、免疫原性、药代动力学、最大耐受剂量及生物分布，该研究针对晚期腺癌患者。
ING-1最初每3周给患者静脉输注1小时。毒性和药代动力学数据促使对每周给药方案进行评估。研究了碘-131（131I）标记的ING-1的分布情况。
25例患者接受了82个疗程的ING-1治疗。最初在0.03、0.10和0.30mg/kg剂量水平观察到最小毒性。一名接受1.0mg/kg剂量的患者发生急性胰腺炎，伴有严重腹痛、恶心和呕吐。一名接受0.3mg/kg剂量的患者淀粉酶和脂肪酶无症状升高，分别升至502单位/L和1,627单位/L。两名患者均顺利康复。未观察到其他剂量限制性毒性。无论剂量如何，分布容积（平均值±标准误）为46.6±1.6mL/kg。ING-1清除率随剂量增加而降低。为使毒性最小化并提高剂量强度，随后我们每周给药ING-1。7名接受0.1mg/kg剂量的患者未观察到明显毒性。131I标记的ING-1生物分布研究显示在结直肠癌和前列腺癌中有放射性定位。一名结直肠癌患者癌胚抗原水平下降了80%。
ING-1的推荐剂量为每周静脉输注0.10mg/kg。该剂量下无严重毒性、低免疫原性以及ING-1肿瘤定位和抗肿瘤疗效的初步证据支持该抗体进一步用于治疗Ep-CAM阳性恶性疾病的临床开发。
