Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies
Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies
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DOI：
10.1158/0008-5472.can-04-0401
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Kerbel, RS
中科院分区：
文献类型：
--
作者：
Bocci, G;Man, S;Kerbel, RS
影响许多新的靶向抗癌药物（包括血管生成抑制剂）成功应用的主要障碍是与确定有效生物/治疗剂量相关的经验主义，因为许多这些药物在最大耐受剂量（如果可以定义最大耐受剂量）以下表现出最佳治疗活性。因此，需要替代标记物来帮助确定最佳剂量。在这里，我们描述了这样一个分子标记，血管内皮生长因子（VEGF）血浆水平升高，在正常或荷瘤小鼠接受注射抗VEGF受体(VEGFR)-2单克隆抗体，如DC101。单次注射DC101后，小鼠VEGF快速增加（例如在24小时内），可达1个数量级；在人荷瘤小鼠中检测到人血浆VEGF的类似增加。另一种抗vegfr -2抗体RAFL-1也引起血浆VEGF显著升高。相比之下，当在正常小鼠中测试小分子VEGFR-2抑制剂时，小鼠VEGF水平未见增加。最重要的是，血浆VEGF的增加是以剂量依赖的方式诱导的，当使用先前确定的最佳治疗剂量时，其最大值达到峰值。血浆VEGF应被视为可能的替代药效学标志物，用于确定在临床环境中阻断VEGFR-2 （KDR）活性的抗体药物的最佳生物剂量。
A major obstacle compromising the successful application of many of the new targeted anticancer drugs, including angiogenesis inhibitors, is the empiricism associated with determining an effective biological/therapeutic dose because many of these drugs express optimum therapeutic activity below the maximum tolerated dose, if such a dose can be defined. Hence, surrogate markers are needed to help determine optimal dosing. Here we describe such a molecular marker, increased plasma levels of vascular endothelial growth factor (VEGF), in normal or tumor-bearing mice that received injections of an anti-VEGF receptor (VEGFR)-2 monoclonal antibody, such as DC101. Rapid increases of mouse VEGF (e.g., within 24 hours) up to 1 order of magnitude were observed after single injections of DC101 in non-tumor-bearing severe combined immunodeficient or nude mice; similar increases in human plasma VEGF were detected in human tumor-bearing mice. RAFL-1, another anti-VEGFR-2 antibody, also caused a significant increase in plasma VEGF. In contrast, increases in mouse VEGF levels were not seen when small molecule VEGFR-2 inhibitors were tested in normal mice. Most importantly, the increases in plasma VEGF were induced in a dose-dependent manner, with the maximum values peaking when doses previously determined to be optimally therapeutic were used. Plasma VEGF should be considered as a possible surrogate pharmacodynamic marker for determining the optimal biological dose of antibody drugs that block VEGFR-2 (KDR) activity in a clinical setting.