Ray Geoffrey L, Baidoo Kwamena E, Keller Lanea M M, Albert Paul S, Brechbiel Martin W, Milenic Diane E
Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
Pharmaceuticals (Basel). 2011 Dec 22;5(1):1-15. doi: 10.3390/ph5010001.
Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of (177)Lu was investigated. The combination of a 6.7 d half-life, lower energy β(-)-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make (177)Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-zparticle radiation. Radiolabeling trastuzumab-CHX-A"-DTPA with (177)Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of (177)Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered (177)Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with (177)Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease.
该实验室的研究已证明，利用具有医学相关性的放射性核素靶向HER2用于治疗和成像应用的潜力。为了扩大曲妥珠单抗作为放射性免疫缀合物（RIC）载体的应用范围，对（177）Lu的使用进行了研究。6.7天的半衰期、较低能量的β（-）发射（最大500 keV；平均130 keV）以及可成像的γ发射的组合，使（177）Lu成为放射性免疫治疗（RIT）方案中一个有吸引力的候选者，用于治疗α粒子辐射无法治疗的较大肿瘤负荷。用（177）Lu对曲妥珠单抗-CHX-A"-DTPA进行放射性标记效率很高，与HER2阳性SKOV-3细胞的特异性结合率为60.8±6.8%。对患有皮下和腹腔内LS-174T异种移植瘤的无胸腺小鼠进行了肿瘤靶向和正常组织摄取的直接定量；分别获得了24.70±10.29（96小时）和31.70±16.20（72小时）的肿瘤%ID/g峰值。RIC在正常组织中的摄取极少。γ闪烁显像也证实了肿瘤靶向性。一项治疗研究对患有腹腔内接种三天的LS-174T异种移植瘤的小鼠给予递增剂量的（177）Lu-曲妥珠单抗，确定腹腔内给予（177）Lu-曲妥珠单抗的有效治疗剂量为375 μCi，中位生存期为124.5天，而对照组（未治疗）的中位生存期为10天。总之，用（177）Lu放射性标记的曲妥珠单抗有治疗播散性HER2阳性腹膜疾病的潜力。
