Delgado C, Pedley R B, Herraez A, Boden R, Boden J A, Keep P A, Chester K A, Fisher D, Begent R H, Francis G E
Molecular Cell Pathology Laboratory, Royal Free Hospital School of Medicine, London, UK.
Br J Cancer. 1996 Jan;73(2):175-82. doi: 10.1038/bjc.1996.32.
Polyethylene glycol (PEG) modification of a chimeric Fab' fragment (F9) of A5B7 (alpha-CEA), using an improved coupling method, increases its specificity for subcutaneous LS174T tumours. PEGylation increased the area under the concentration-time curve (AUC0-144) in all tissues but there were significant differences (variance ratio test, F = 27.95, P < 0.001) between the proportional increases in AUC0-144, with the tumour showing the greatest increase. The increase in AUCtumour from F9 to PEG-F9 was similar to the reported increase from Fab' to F(ab')2 while the increase in AUCblood by PEGylation of F9 was only 21% of the reported increase from Fab' to whole IgG. A two sample t-test showed no significant differences between maximal tumour/tissue ratios for PEG-F9 and F9 while the tumour/tissue ratios for PEG-F9 remained high over a longer period, with tumour levels at least double those for F9. PEG-F9 emerges as a new generation antibody with potential advantages for both radioimmunotherapy and tumour imaging. Since there was a reduction in antigen binding, optimisation of PEGylation might further improve tumour specificity. The latter resulted from complex effects on both the entry into and exit rates from tumour and normal tissues in a tissue-specific fashion.
采用改进的偶联方法对A5B7（α-癌胚抗原）嵌合Fab'片段（F9）进行聚乙二醇（PEG）修饰，可提高其对皮下LS174T肿瘤的特异性。PEG化使所有组织中的浓度-时间曲线下面积（AUC0-144）增加，但AUC0-144的比例增加之间存在显著差异（方差比检验，F = 27.95，P < 0.001），肿瘤的增加最为显著。从F9到PEG-F9，肿瘤的AUC增加与报道的从Fab'到F(ab')2的增加相似，而F9经PEG化后血液中的AUC增加仅为报道的从Fab'到完整IgG增加的21%。两样本t检验显示PEG-F9和F9的最大肿瘤/组织比率之间无显著差异，而PEG-F9的肿瘤/组织比率在更长时间内保持较高水平，肿瘤水平至少是F9的两倍。PEG-F9成为一种新一代抗体，在放射免疫治疗和肿瘤成像方面具有潜在优势。由于抗原结合减少，PEG化的优化可能会进一步提高肿瘤特异性。后者是由对肿瘤和正常组织的进入和退出速率以组织特异性方式产生的复杂影响导致的。
