Translational Research Group in Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA.
Clin Cancer Res. 2010 Nov 1;16(21):5177-88. doi: 10.1158/1078-0432.CCR-10-1343. Epub 2010 Sep 9.
P-cadherin is a membrane glycoprotein that functionally mediates tumor cell adhesion, proliferation, and invasiveness. We characterized the biological properties of PF-03732010, a human monoclonal antibody against P-cadherin, in cell-based assays and tumor models.
The affinity, selectivity, and cellular inhibitory activity of PF-03732010 were tested in vitro. Multiple orthotopic and metastatic tumor models were used for assessing the antitumor and antimetastatic activities of PF-03732010. Treatment-associated pharmacodynamic changes were also investigated.
PF-03732010 selectively inhibits P-cadherin-mediated cell adhesion and aggregation in vitro. In the P-cadherin-overexpressing tumor models, including MDA-MB-231-CDH3, 4T1-CDH3, MDA-MB-435HAL-CDH3, HCT116, H1650, PC3M-CDH3, and DU145, PF-03732010 inhibited the growth of primary tumors and metastatic progression, as determined by bioluminescence imaging. Computed tomography imaging, H&E stain, and quantitative PCR analysis confirmed the antimetastatic activity of PF-03732010. In contrast, PF-03732010 did not show antitumor and antimetastatic efficacy in the counterpart tumor models exhibiting low P-cadherin expression. Mechanistic studies via immunofluorescence, immunohistochemical analyses, and 3'-[(18)F]fluoro-3'-deoxythymidine-positron emission tomography imaging revealed that PF-03732010 suppressed P-cadherin levels, caused degradation of membrane β-catenin, and concurrently suppressed cytoplasmic vimentin, resulting in diminished metastatic capacity. Changes in the levels of Ki67, caspase-3, and 3'-[(18)F]fluoro-3'-deoxythymidine tracer uptake also indicated antiproliferative activity and increased apoptosis in the tested xenografts.
These findings suggest that interrupting the P-cadherin signaling pathway may be a novel therapeutic approach for cancer therapy. PF-03732010 is presently undergoing evaluation in Phase 1 clinical trials.
P 钙黏蛋白是一种膜糖蛋白，可在细胞黏附、增殖和侵袭中发挥功能。我们在细胞实验和肿瘤模型中对人源单克隆抗体 PF-03732010 针对 P 钙黏蛋白的生物学特性进行了鉴定。
在体外测试了 PF-03732010 的亲和力、选择性和细胞抑制活性。采用多种原位和转移性肿瘤模型评估 PF-03732010 的抗肿瘤和抗转移活性。还研究了治疗相关的药效学变化。
PF-03732010 可选择性抑制体外 P 钙黏蛋白介导的细胞黏附和聚集。在 P 钙黏蛋白过表达的肿瘤模型中，包括 MDA-MB-231-CDH3、4T1-CDH3、MDA-MB-435HAL-CDH3、HCT116、H1650、PC3M-CDH3 和 DU145，PF-03732010 通过生物发光成像抑制了原发性肿瘤的生长和转移进展。计算机断层扫描成像、H&E 染色和定量 PCR 分析证实了 PF-03732010 的抗转移活性。相比之下，在 P 钙黏蛋白表达水平较低的对照肿瘤模型中，PF-03732010 未显示出抗肿瘤和抗转移疗效。通过免疫荧光、免疫组化分析和 3'-[(18)F]氟-3'-脱氧胸苷正电子发射断层扫描成像进行的机制研究表明，PF-03732010 抑制 P 钙黏蛋白水平，导致膜 β-连环蛋白降解，并同时抑制细胞质波形蛋白，从而降低转移能力。Ki67、caspase-3 和 3'-[(18)F]氟-3'-脱氧胸苷示踪剂摄取水平的变化也表明，在测试的异种移植物中存在抗增殖活性和增加的细胞凋亡。
这些发现表明，阻断 P 钙黏蛋白信号通路可能是癌症治疗的一种新的治疗方法。PF-03732010 目前正在进行 I 期临床试验评估。
