Vallera Daniel A, Sicheneder Andy R, Taras Elizabeth P, Brechbiel Martin W, Vallera Jesse A, Panoskaltsis-Mortari Angela, Burns Linda J
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
Cancer Biother Radiopharm. 2007 Aug;22(4):488-500. doi: 10.1089/cbr.2007.366.
Studies were performed to determine the suitability of using the polyethylene glycol (PEG)-labeled AHN-12 anti-CD45 monoclonal antibody to deliver the high-energy beta-particle-emitting isotope 90Y to a CD45+ B-cell Daudi lymphoma grown as flank tumors in athymic nude mice. The PEGylated radiolabeled antibody displayed a significantly better antitumor effect in the mouse tumor flank model (p<0.03) and significantly better blood pharmacokinetics in normal rats (p<0.05) than the non-PEGylated radiolabeled antibody. Studies of two different sizes of PEG showed that rats given 43 kDa of PEGylated AHN-12, but not 5 kDa of PEGylated AHN-12, had significantly higher radiolabeled antibody blood levels and, therefore, improved pharmacokinetics, as compared to rodents given non-PEGylated radiolabeled AHN-12 (p<0.05). Surviving mice revealed no signs of kidney, liver, or gastrointestinal damage by histology study. Notably, in vitro studies indicated that PEGylation did not have a major effect on labeling efficiency and the binding of labeled antibody. These findings indicate that PEGylation of radiolabeled anti-CD45 antibody may be a useful and desirable means of extending blood half-life and enhancing efficacy. Also, the final outcome may be impacted by the size of the PEG molecule used for the modification of the blood half-life.
开展了多项研究，以确定使用聚乙二醇（PEG）标记的AHN-12抗CD45单克隆抗体，将发射高能β粒子的同位素90Y递送至在无胸腺裸鼠胁腹生长的CD45+B细胞Daudi淋巴瘤的适用性。与未聚乙二醇化的放射性标记抗体相比，聚乙二醇化的放射性标记抗体在小鼠肿瘤胁腹模型中显示出显著更好的抗肿瘤效果（p<0.03），在正常大鼠中具有显著更好的血液药代动力学（p<0.05）。对两种不同大小PEG的研究表明，与给予未聚乙二醇化放射性标记AHN-12的啮齿动物相比，给予43 kDa聚乙二醇化AHN-12的大鼠（而非5 kDa聚乙二醇化AHN-12的大鼠）具有显著更高的放射性标记抗体血药浓度，因此药代动力学得到改善（p<0.05）。通过组织学研究，存活小鼠未显示出肾脏、肝脏或胃肠道损伤的迹象。值得注意的是，体外研究表明聚乙二醇化对标记效率和标记抗体的结合没有重大影响。这些发现表明，放射性标记抗CD45抗体的聚乙二醇化可能是延长血液半衰期和提高疗效的一种有用且理想的方法。此外，最终结果可能会受到用于修饰血液半衰期的PEG分子大小的影响。
