Mordenti J, Thomsen K, Licko V, Chen H, Meng Y G, Ferrara N
Experimental Therapeutics, Genentech, Inc., South San Francisco, California 94080, USA.
Toxicol Pathol. 1999 Jan-Feb;27(1):14-21. doi: 10.1177/019262339902700104.
The development of a neovascular supply (angiogenesis) is a major aspect of tumorigenesis. Recent work has indicated that vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis. In vitro and in vivo studies have demonstrated that an anti-VEGF antibody is capable of suppressing the growth of human tumor cell lines. The following study was conducted in tumor-bearing nude mice to evaluate the concentration-response relationship of murine anti-VEGF monoclonal antibody (muMAb VEGF) so that an efficacious plasma concentration of the recombinant humanized form (rhuMAb VEGF) in cancer patients could be estimated. (This study was included in our Investigational New Drug application to support the clinical dosing regimen and projected human safety factors for the toxicology program.) Additionally, the growth dynamics of the tumors were evaluated as a function of dose to explore whether a mechanismic interpretation of tumor growth inhibition by muMAb VEGF is possible. On day 1, A673 human rhabdomyosarcoma cells (2 x 10(6) cells/mouse) were injected subcutaneously in 188 beige nude mice (16-24 g). Treatment with muMAb VEGF (0.05-5.0 mg/kg; n = 24/group), phosphate-buffered saline (n = 10), or anti-gp120 isotype-matched control antibody (5.0 mg/kg; n = 10) began 24 hr later. Each animal received intraperitoneal injections of test material twice weekly for 4 wk. Immediately prior to each dose, 2 mice from each muMAb VEGF group were selected randomly, and plasma was collected for pharmacokinetic evaluation; at the end of the study, samples were collected from all animals for pharmacokinetic evaluation. Tumor dimensions were recorded weekly, and at the end of the study, tumor weight and dimensions were recorded. Satisfactory tumor suppression in nude mice was achieved at muMAb VEGF doses of > or =2.5 mg/kg, where the average trough muMAb VEGF plasma concentration was 30 microg/ml (concentrations in individual animals >10 microg/ml). Assuming the pharmacokinetics of rhuMAb VEGF in patients will resemble the pharmacokinetics of a similar humanized anticancer monoclonal antibodies, a clinical dosing regimen was designed to maintain the rhuMAb VEGF plasma concentration in this efficacious range. This study shows an approach that can be used to estimate a human dosing regimen from preclinical pharmacokinetic/pharmacodynamic data. Because we have just initiated clinical trials with rhuMAb VEGF we cannot judge clinical outcome in relation to these preclinical predictions; nonetheless, it is hoped that by sharing our approach and thought processes with other investigators we can assist the discovery and development of anticancer therapeutics.
新生血管供应的形成（血管生成）是肿瘤发生的一个主要方面。最近的研究表明，血管内皮生长因子（VEGF）是血管生成的主要调节因子。体外和体内研究均已证明，抗VEGF抗体能够抑制人肿瘤细胞系的生长。以下研究在荷瘤裸鼠中进行，以评估鼠抗VEGF单克隆抗体（muMAb VEGF）的浓度-反应关系，从而估计重组人源化形式（rhuMAb VEGF）在癌症患者中的有效血浆浓度。（本研究已纳入我们的研究性新药申请，以支持临床给药方案和毒理学计划的预计人体安全因素。）此外，评估肿瘤的生长动力学与剂量的关系，以探讨是否有可能对muMAb VEGF抑制肿瘤生长的机制进行解释。在第1天，将A673人横纹肌肉瘤细胞（2×10⁶个细胞/只小鼠）皮下注射到188只米色裸鼠（16 - 24 g）体内。24小时后开始用muMAb VEGF（0.05 - 5.0 mg/kg；每组n = 24）、磷酸盐缓冲盐水（每组n = 10）或抗gp120同种型匹配对照抗体（5.0 mg/kg；每组n = 10）进行治疗。每只动物每周接受两次腹腔注射受试物，共4周。在每次给药前，从每个muMAb VEGF组中随机挑选2只小鼠，采集血浆进行药代动力学评估；在研究结束时，从所有动物中采集样本进行药代动力学评估。每周记录肿瘤大小，在研究结束时，记录肿瘤重量和大小。当muMAb VEGF剂量≥2.5 mg/kg时，在裸鼠中实现了满意的肿瘤抑制效果，此时muMAb VEGF的平均谷值血浆浓度为30 μg/ml（个别动物浓度>10 μg/ml）。假设rhuMAb VEGF在患者中的药代动力学将类似于类似人源化抗癌单克隆抗体的药代动力学，设计了临床给药方案以将rhuMAb VEGF血浆浓度维持在这个有效范围内。本研究展示了一种可用于从临床前药代动力学/药效学数据估计人体给药方案的方法。由于我们刚刚开始用rhuMAb VEGF进行临床试验，我们无法判断与这些临床前预测相关的临床结果；尽管如此，希望通过与其他研究人员分享我们的方法和思维过程，我们能够协助抗癌治疗药物的发现和开发。
