Leung Kam
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Angiogenesis is an essential process in the development of new blood vessels both in normal physiological states and diseases (1, 2). Targeting of tumor vasculature is a promising strategy for tumor imaging and therapy because tumor growth and metastasis largely depend on angiogenesis (3-5). Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that modulates blood vessel development, angiogenesis, and tumor progression (6). There are three isoforms of TGF-β (β, β, and β). TGF-β inhibits proliferation and migration of endothelial cells and their ability to form capillaries. CD105 (endoglin, EDG) is a homodimeric transmembrane glycoprotein (180 kDa) with disulfide-linked subunits of 95,000. CD105 is a component of the TGF-β receptor complex that specifically binds TGF-β and TGF-β with high affinity (7). CD105 is important for blood vessel development. The expression of CD105 on different cells affects cellular response to TGF-β. CD105 is overexpressed in proliferating endothelial cells of tumor vessels, and CD105 prevents TGF-β–mediated inhibition of endothelial cell proliferation (8, 9). Radiolabeled monoclonal antibodies (mAbs) have been developed for both the diagnosis and treatment of tumors (10-12). Quiescent human endothelial cells express CD105 only weakly, but the expression of CD105 is strongly upregulated on the endothelial cells of tumor tissues undergoing angiogenesis (9, 13). The high level of expressed CD105 (up to 10 molecules/proliferating cell) appears to be ideal for imaging and therapy. Anti-CD105 mAbs, such as MAEND3, E9, and MJ7/18 with radioisotopes (e.g., In, Tc, and I) have been studied as single-photon emission computed tomography (SPECT) probes for imaging CD105 expression (9, 14). TRC105 is a human/murine chimeric IgG mAb that binds with higher affinity to human CD105 than to murine CD105 (15). TRC105 inhibits angiogenesis and tumor growth and is now in clinical trials in cancer patients. Binding of TRC105 to CD105 allows TGF-β–mediated inhibition of endothelial cell proliferation. Hong et al. (16) showed that Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-anti-CD105 TRC105 (Cu-DOTA-TRC105) mAb could efficiently image 4T1 murine breast tumor in mice with positron emission tomography (PET) imaging. Hong et al. (17) have evaluated Zr-desferrioxamine-TRC105 (Zr-Df-TRC105) as an Zr-based PET agent in the same 4T1 murine breast tumor model. For near-infrared (NIR) fluorescence optical imaging, Yang et al. (18) conjugated IRDye800CW to TRC105 to form IRDye800CW-TRC105 to assess CD105 expression in mice bearing 4T1 murine breast tumors.
血管生成是正常生理状态和疾病中新生血管发育的一个重要过程(1,2)。靶向肿瘤血管系统是肿瘤成像和治疗的一种有前景的策略，因为肿瘤生长和转移很大程度上依赖于血管生成(3 - 5)。转化生长因子-β（TGF-β）是一种多效性细胞因子，可调节血管发育、血管生成和肿瘤进展(6)。TGF-β有三种亚型（β1、β2和β3）。TGF-β抑制内皮细胞的增殖和迁移及其形成毛细血管的能力。CD105（内皮糖蛋白，EDG）是一种同二聚体跨膜糖蛋白（180 kDa），由95,000的二硫键连接亚基组成。CD105是TGF-β受体复合物的一个组成部分，它以高亲和力特异性结合TGF-β1和TGF-β3(7)。CD105对血管发育很重要。CD105在不同细胞上的表达影响细胞对TGF-β的反应。CD105在肿瘤血管的增殖内皮细胞中过表达，并且CD105可防止TGF-β介导的内皮细胞增殖抑制(8,9)。放射性标记的单克隆抗体（mAb）已被开发用于肿瘤的诊断和治疗(10 - 12)。静止的人内皮细胞仅微弱表达CD105，但在经历血管生成的肿瘤组织的内皮细胞上，CD105的表达强烈上调(9,13)。高水平表达的CD105（高达10个分子/增殖细胞）似乎是成像和治疗的理想选择。抗CD105 mAb，如带有放射性同位素（如铟、锝和碘）的MAEND3、E9和MJ7/18，已被研究作为用于成像CD105表达的单光子发射计算机断层扫描（SPECT）探针(9,14)。TRC105是一种人/鼠嵌合IgG mAb，它与人CD105的结合亲和力高于与鼠CD105的结合亲和力(15)。TRC105抑制血管生成和肿瘤生长，目前正在癌症患者中进行临床试验。TRC105与CD105的结合允许TGF-β介导的内皮细胞增殖抑制。Hong等人(16)表明，铜-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-抗CD105 TRC105（Cu-DOTA-TRC105）mAb可通过正电子发射断层扫描（PET）成像在小鼠中有效成像4T1小鼠乳腺肿瘤。Hong等人(17)在相同的4T1小鼠乳腺肿瘤模型中评估了锆-去铁胺-TRC105（Zr-Df-TRC105）作为一种基于锆的PET剂。对于近红外（NIR）荧光光学成像，Yang等人(18)将IRDye800CW与TRC105偶联以形成IRDye800CW-TRC105，以评估携带4T1小鼠乳腺肿瘤的小鼠中的CD105表达。
