Combination photoimmunotherapy with monoclonal antibodies recognizing different epitopes of human epidermal growth factor receptor 2: an assessment of phototherapeutic effect based on fluorescence molecular imaging.
Combination photoimmunotherapy with monoclonal antibodies recognizing different epitopes of human epidermal growth factor receptor 2: an assessment of phototherapeutic effect based on fluorescence molecular imaging.
复制标题
DOI：
10.18632/oncotarget.7490
复制
发表时间：
2016-03-22
期刊：
影响因子：
--
通讯作者：
Tajiri H
中科院分区：
文献类型：
--
作者：
Ito K;Mitsunaga M;Nishimura T;Kobayashi H;Tajiri H
光免疫疗法是一种新型的分子靶向癌症疗法，其基于与光敏剂缀合的单克隆抗体（mAb）和用于成像和治疗的近红外（NIR）光照射。在这里，我们试图确定使用人表皮生长因子受体2（HER 2）特异性mAb-光敏剂IR 700、曲妥珠单抗-IR 700和帕妥珠单抗-IR 700的缀合物组合光免疫疗法的可行性。用mAb-IR 700缀合物处理HER 2表达和非表达细胞，并用NIR光照射。在培养的HER 2表达癌细胞系和小鼠肿瘤异种移植模型中检查荧光成像和细胞毒性作用。曲妥珠单抗-IR 700和帕妥珠单抗-IR 700可以特异性结合HER 2而不竞争，并且两种药物的联合治疗产生的HER 2特异性IR 700荧光信号比单独使用任何一种药物的治疗更强。细胞毒性试验表明，曲妥珠单抗-IR 700和帕妥珠单抗-IR 700联合处理后再进行NIR光照射诱导的细胞毒性效应比任一种药物加NIR光照射的处理更强。此外，mAb的光毒性和细胞毒性作用取决于HER 2特异性IR 700信号强度。与体外研究一致，在异种移植肿瘤模型中，曲妥珠单抗-IR 700和帕妥珠单抗-IR 700联合治疗后IR 700荧光成像引导的近红外光照射比用任一药物治疗后再进行近红外光照射产生更强的抗肿瘤作用。总之，荧光分子成像可以促进分子靶向光免疫治疗的治疗结果的评估，这在促进癌症患者更好的结果方面具有很大的潜力。
Photoimmunotherapy is a new class of molecular targeted cancer therapy based on a monoclonal antibody (mAb) conjugated to a photosensitizer and irradiation with near-infrared (NIR) light for both imaging and therapy. Here, we sought to determine the feasibility of combining photoimmunotherapy using conjugates of human epidermal growth factor receptor 2 (HER2)-specific mAb-photosensitizer IR700, trastuzumab-IR700 and pertuzumab-IR700. HER2-expressing and non-expressing cells were treated with mAb-IR700 conjugates and irradiated with NIR light. Fluorescence imaging and cytotoxic effects were examined in cultured HER2-expressng cancer cell lines and in a mouse tumor xenograft model. Trastuzumab-IR700 and pertuzumab-IR700 could specifically bind to HER2 without competing, and the combination treatment of both agents yielded stronger HER2-specific IR700 fluorescence signals than with the treatment with either agent singly. A cytotoxicity assay showed that the combination treatment of both trastuzumab-IR700 and pertuzumab-IR700 followed by NIR light irradiation induced stronger cytotoxic effect than with treatment of either agent plus NIR light irradiation. Furthermore, the phototoxic and cytotoxic effects of mAb depended on HER2-specific IR700 signal intensities. Consistent with in vitro studies, in xenograft tumor models also, IR700 fluorescence imaging-guided NIR light irradiation after the combination treatment of trastuzumab-IR700 and pertuzumab-IR700 led to stronger antitumor effects than by treatment with either agent followed by NIR light irradiation. In conclusion, fluorescence molecular imaging can facilitate the assessment of treatment outcomes of molecular targeted photoimmunotherapy, which holds great potential in facilitating better outcomes in cancer patients.