VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade
VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade
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DOI：
10.1073/pnas.0708865104
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发表时间：
2007-11-20
影响因子：
11.1
通讯作者：
Yancopoulos, George D.
中科院分区：
文献类型：
--
作者：
Rudge, John S.;Holash, Jocelyn;Yancopoulos, George D.
VEGF 是最具特征的肿瘤血管生成介质。抗 VEGF 药物最近在人类癌症试验中显示出令人印象深刻的功效，但此类药物的最佳剂量仍必须凭经验确定，因为指导剂量的生物标志物尚未建立。人们广泛接受（但未经证实）的假设是，正常成年人中 VEGF 的产生量相当低，这导致了这样一种观点：全身 VEGF 水平的增加可能定量地反映了肿瘤质量和血管生成活性。我们描述了一种确定宿主和肿瘤产生 VEGF 的方法，使用目前正在进行临床试验的高亲和力和长寿命 VEGF 拮抗剂 VEGF Trap。与通常快速清除的抗体复合物不同，VEGF Trap 与组织和肿瘤来源的 VEGF 形成惰性复合物，这些复合物稳定地保留在体循环中，易于检测，从而提供了前所未有的准确测量 VEGF 产生的能力。我们报告说，在非肿瘤啮齿动物和人类中，VEGF 的产生量出人意料地高，这挑战了全身 VEGF 水平可以作为肿瘤负荷的敏感替代指标的观念；肿瘤 VEGF 的贡献仅在肿瘤负荷非常大时才变得显着。这些发现有一个重要的推论，即抗 VEGF 疗法的剂量必须足够，以避免被宿主衍生的 VEGF 转移。我们进一步表明，我们的测定可以指示 VEGF 何时被最佳阻断；其他抗 VEGF 药物不存在此类指导剂量的生物标志物。根据该测定，目前正在临床试验中评估的 VEGF Trap 剂量在上述范围内。
VEGF is the best characterized mediator of tumor angiogenesis. Anti-VEGF agents have recently demonstrated impressive efficacy in human cancer trials, but the optimal dosing of such agents must still be determined empirically, because biomarkers to guide dosing have yet to be established. The widely accepted (but unverified) assumption that VEGF production is quite low in normal adults led to the notion that increased systemic VEGF levels might quantitatively reflect tumor mass and angiogenic activity. We describe an approach to determine host and tumor production of VEGF, using a high-affinity and long-lived VEGF antagonist now in clinical trials, the VEGF Trap. Unlike antibody complexes that are usually rapidly cleared, the VEGF Trap forms inert complexes with tissue- and tumor-derived VEGF that remain stably in the systemic circulation, where they are readily assayable, providing unprecedented capability to accurately measure VEGF production. We report that VEGF production is surprisingly high in non-tumor-bearing rodents and humans, challenging the notion that systemic VEGF levels can serve as a sensitive surrogate for tumor load; tumor VEGF contribution becomes significant only with very large tumor loads. These findings have the important corollary that anti-VEGF therapies must be sufficiently dosed to avoid diversion by host-derived VEGF. We further show that our assay can indicate when VEGF is optimally blocked; such biomarkers to guide dosing do not exist for other anti-VEGF agents. Based on this assay, VEGF Trap doses currently being assessed in clinical trials are in thee range.