Scott Andrew M, Tebbutt Niall, Lee Fook-Thean, Cavicchiolo Tina, Liu Zhanqi, Gill Sanjeev, Poon Aurora M T, Hopkins Wendie, Smyth Fiona E, Murone Carmel, MacGregor Duncan, Papenfuss Anthony T, Chappell Bridget, Saunder Timothy H, Brechbiel Martin W, Davis Ian D, Murphy Roger, Chong Geoffrey, Hoffman Eric W, Old Lloyd J
Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Austin Hospital, Australia.
Clin Cancer Res. 2007 Jun 1;13(11):3286-92. doi: 10.1158/1078-0432.CCR-07-0284.
We report a first-in-man trial of a humanized antibody (hu3S193) against the Le(y) antigen.
Patients with advanced Le(y)-positive cancers received four infusions of hu3S193 at weekly intervals, with four dose levels (5, 10, 20, and 40 mg/m(2)). The first infusion of hu3S193 was trace labeled with Indium-111, and biodistribution, pharmacokinetics, tumor uptake, and immune response were evaluated in all patients.
A total of 15 patients (7 male/8 female; age range, 42-76 years; 6 breast, 8 colorectal cancer, and 1 non-small-cell lung cancer) were entered into the study. Transient grade 1 to 2 nausea and vomiting was observed following infusion of hu3S193 at the 40 mg/m(2) dose level only. There was one episode of dose-limiting toxicity with self-limiting Common Toxicity Criteria grade 3 elevated alkaline phosphatase observed in one patient with extensive liver metastases. The biodistribution of (111)In-hu3S193 showed no evidence of any consistent normal tissue uptake, and (111)In-hu3S193 uptake was observed in cutaneous, lymph node, and hepatic metastases. Hu3S193 displayed a long serum half-life (T(1/2)beta = 189.63 +/- 62.17 h). Clinical responses consisted of 4 patients with stable disease and 11 patients with progressive disease, although one patient experienced a 89% decrease in a lymph node mass, and one patient experienced inflammatory symptoms in cutaneous metastases, suggestive of a biological effect of hu3S193. No immune responses (human anti-human antibody) to hu3S193 were observed.
Hu3S193 is well tolerated and selectively targets tumors, and the long half-life and biological function in vivo of this antibody makes it an attractive potential therapy for patients with Le(y)-expressing cancers.
我们报告了一项针对抗Le(y)抗原的人源化抗体（hu3S193）的首次人体试验。
晚期Le(y)阳性癌症患者每隔一周接受4次hu3S193输注，有4个剂量水平（5、10、20和40mg/m²）。首次输注的hu3S193用铟-111进行微量标记，对所有患者评估生物分布、药代动力学、肿瘤摄取和免疫反应。
共有15名患者（7名男性/8名女性；年龄范围42 - 76岁；6例乳腺癌、8例结直肠癌和1例非小细胞肺癌）进入该研究。仅在40mg/m²剂量水平输注hu3S193后观察到短暂的1至2级恶心和呕吐。有1例剂量限制性毒性事件，在1例有广泛肝转移的患者中观察到自限性的常见毒性标准3级碱性磷酸酶升高。铟-111标记的hu3S193的生物分布未显示任何一致的正常组织摄取证据，在皮肤、淋巴结和肝转移灶中观察到铟-111标记的hu3S193摄取。Hu3S193显示出较长的血清半衰期（T(1/2)β = 189.63 ± 62.17小时）。临床反应包括4例病情稳定的患者和11例病情进展的患者，尽管有1例患者的淋巴结肿块减少了89%，1例患者的皮肤转移灶出现炎症症状，提示hu3S193有生物学效应。未观察到对hu3S193的免疫反应（人抗人抗体）。
Hu3S193耐受性良好且能选择性靶向肿瘤，该抗体在体内的长半衰期和生物学功能使其成为表达Le(y)癌症患者有吸引力的潜在治疗方法。
