Antoniw P, Farnsworth A P, Turner A, Haines A M, Mountain A, Mackintosh J, Shochat D, Humm J, Welt S, Old L J, Yarranton G T, King D J
Celltech Therapeutics Ltd., Slough, Berks, UK.
Br J Cancer. 1996 Aug;74(4):513-24. doi: 10.1038/bjc.1996.395.
The monoclonal antibody A33 recognises a tumour-associated antigen on human colorectal carcinoma, and has undergone preliminary evaluation in the clinic where selective localisation to hepatic metastases has been demonstrated [Welt et al. (1994) J. Clin. Oncol. 12, 1561-1571]. A33 and an A33 tri-fab fragment (TFM) were labelled with 90Y via a stable macrocyclic ligand for biodistribution and therapy studies in nude mice bearing SW1222 colon carcinoma xenografts. Biodistribution studies demonstrated tumour localisation for both A33 IgG and TFM with low bone, liver and kidney levels. Clearance of TFM from the blood was much faster than IgG and this led to lower tumour accumulation for TFM but superior tumour-blood ratios. The maximum per cent injected dose per g localised to tumour was 35.9% +/- 5.3% for A33 IgG and 12.9% +/- 4.6% for A33 TFM with tumour-blood ratios at 48 h after administration of 5.6 +/- 1.8 and 29.2 +/- 9.8 respectively. Autoradiography studies with 125I-labelled A33 IgG and TFM demonstrated a homogeneous distribution within tumour tissue which was not observed with other anti-colorectal tumour antibodies. TFM penetrated into the tumour tissue more rapidly than IgG. In therapy studies, a single dose of 90Y-A33 IgG (250 microCi per mouse) or 90Y-A33 TFM (300 microCi per mouse) led to complete regression of 2-week-old tumour xenografts with long-term tumour-free survivors. A transient drop in white blood cell count was observed with both IgG and TFM but was significantly more pronounced with IgG. The cell count fell to 8.4% of control for IgG, whereas with TFM cell counts fell to 51% of control before recovery. These results indicate that the more rapid blood clearance of 90Y-TFM confers reduced toxicity compared with 90Y-IgG although similar therapeutic effects are achieved. When the dose of 90Y-IgG was adjusted to give the same dose to tumour achieved with 300 microCi 90Y-TFM, a lesser therapeutic effect was observed. This may be owing to more rapid tumour penetration achieved with TFM. Both A33 IgG and TFM demonstrated potent anti-tumour effects against human tumour xenografts in this mouse model system. The stability of these 90Y-labelled conjugates and their effective tumour penetration are promising for the development of humanised reagents for clinical studies.
单克隆抗体A33可识别人类结肠直肠癌上的一种肿瘤相关抗原，并已在临床上进行了初步评估，结果显示其可选择性地在肝转移灶中定位[韦尔特等人（1994年）《临床肿瘤学杂志》12卷，第1561 - 1571页]。通过一种稳定的大环配体将A33和A33三价抗原结合片段（TFM）用90钇进行标记，用于在携带SW1222结肠癌异种移植瘤的裸鼠体内进行生物分布和治疗研究。生物分布研究表明，A33 IgG和TFM均能在肿瘤中定位，且在骨骼、肝脏和肾脏中的含量较低。TFM从血液中的清除速度比IgG快得多，这导致TFM在肿瘤中的蓄积量较低，但肿瘤与血液的比值更高。A33 IgG每克肿瘤组织摄取的最大注射剂量百分比为35.9%±5.3%，A33 TFM为12.9%±4.6%，给药后48小时的肿瘤与血液比值分别为5.6±1.8和29.2±9.8。用125碘标记的A33 IgG和TFM进行的放射自显影研究表明，肿瘤组织内分布均匀，这是其他抗结肠直肠癌抗体所没有的现象。TFM比IgG更快地渗透到肿瘤组织中。在治疗研究中，单剂量的90钇 - A33 IgG（每只小鼠250微居里）或90钇 - A33 TFM（每只小鼠300微居里）可使2周龄的肿瘤异种移植瘤完全消退，且有长期无瘤存活者。IgG和TFM均观察到白细胞计数短暂下降，但IgG更为明显。IgG组细胞计数降至对照组的8.4%，而TFM组细胞计数在恢复前降至对照组的51%。这些结果表明，与90钇 - IgG相比，90钇 - TFM更快的血液清除率使其毒性降低，尽管两者的治疗效果相似。当将90钇 - IgG的剂量调整为与300微居里90钇 - TFM给予肿瘤的相同剂量时，观察到的治疗效果较差。这可能是由于TFM能更快地渗透到肿瘤中。在该小鼠模型系统中,A33 IgG和TFM均对人肿瘤异种移植瘤显示出强大的抗肿瘤作用。这些90钇标记的偶联物的稳定性及其有效的肿瘤渗透能力，对于开发用于临床研究的人源化试剂很有前景。
