Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: a phase I, pharmacokinetic, and biological correlative study.
Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: a phase I, pharmacokinetic, and biological correlative study.
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DOI：
10.1158/1078-0432.ccr-08-0378
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Wilding G
中科院分区：
文献类型：
--
作者：
Ricart AD;Tolcher AW;Liu G;Holen K;Schwartz G;Albertini M;Weiss G;Yazji S;Ng C;Wilding G
本研究旨在评估Volociximab（一种特异性结合α5β1整联蛋白的嵌合单克隆抗体）给药的安全性和可行性，并确定药代动力学、药效学和抗肿瘤活性的初步证据。晚期实体恶性肿瘤患者在60分钟内接受递增剂量的volociximab i. v.治疗。分析血液样品以确定血浆药代动力学参数，检测人抗嵌合抗体形成，并确定外周血单核细胞上α5β1位点的饱和度。21例患者在第1、15、22、29和36天接受了223次volociximab输注，剂量范围为0.5 - 15 mg/kg i. v.;此后每周一次。治疗耐受性良好，在检查的范围内未发现剂量限制性毒性。在最高剂量水平10和15 mg/kg下，轻度（1级或2级）可逆性疲劳是volociximab的主要毒性。恶心、发热、厌食、头痛、呕吐和肌痛轻微且罕见，无血液学毒性。Volociximab呈双指数分布;清除率与剂量增加呈负相关，15 mg/kg剂量下的半衰期估计为30天。三名患者检测抗volociximab抗体阳性。单核细胞α5β1整联蛋白位点的饱和度呈剂量依赖性，剂量高达15 mg/kg。有1例轻微缓解（肾脏，7个月）和1例持续稳定疾病（黑色素瘤，14个月）。Volociximab可以安全地以每周15 mg/kg i. v.给药。在最高剂量水平下不存在严重毒性和初步活性，因此需要进行进一步的疾病导向研究。
This study aimed to assess the safety and feasibility of administering volociximab, a chimeric monoclonal antibody that specifically binds to α5β1 integrin, and to determine the pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity. Patients with advanced solid malignancies were treated with escalating doses of volociximab i.v. administered over 60 minutes. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human antichimeric antibody formation, and determine the saturation of α5β1 sites on peripheral blood monocytes. Twenty-one patients received 223 infusions of volociximab at doses ranging from 0.5 to 15 mg/kg i.v. on days 1, 15, 22, 29, and 36; and weekly thereafter. Treatment was well tolerated, and dose-limiting toxicity was not identified over the range examined. Mild (grade 1 or 2), reversible fatigue was the principal toxicity of volociximab at the highest dose levels of 10 and 15 mg/kg. Nausea, fever, anorexia, headache, vomiting, and myalgias were mild and infrequent, and there was no hematologic toxicity. Volociximab had biexponential distribution; clearance was inversely related to increasing dose, and the half-life at 15 mg/kg was estimated as being 30 days. Three patients tested positive for anti-volociximab antibodies. Saturation of monocyte α5β1 integrin sites was dose-dependent up to 15 mg/kg. There was one minor response (renal, 7 months) and one durable stable disease (melanoma, 14 months). Volociximab can be safely administered at 15 mg/kg i.v. per week. The absence of severe toxicities and preliminary activity at the highest dose level warrants further disease-directed studies.