Wong J Y, Thomas G E, Yamauchi D, Williams L E, Odom-Maryon T L, Liu A, Esteban J M, Neumaier M, Dresse S, Wu A M, Primus F J, Shively J E, Raubitschek A A
Division of Radiation Oncology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California 91010, USA.
J Nucl Med. 1997 Dec;38(12):1951-9.
Chimeric T84.66 (cT84.66) is a high-affinity (1.16 x 10[11] M[-1]) IgG1 monoclonal antibody (MAb) against carcinoembryonic antigen (CEA). This pilot trial evaluated the tumor-targeting properties, biodistribution, pharmacokinetics and immunogenicity of 111In-labeled cT84.66.
Patients with CEA-producing metastatic malignancies were administered a single intravenous dose of 5 mCi 111In-diethylenetriaminepentaacetic acid-cT84.66. Serial blood samples, 24-hr urine collections and nuclear images were collected up to 7 days postinfusion. Human antichimeric antibody response was assessed up to 6 mo postinfusion.
Imaging of at least one known tumor site was observed in 14 of 15 (93%) patients. Seventy-four lesions were analyzed with an imaging sensitivity rate of 45.1% and a positive predictive value of 94.1%. In one patient, two additional bone metastases developed within 6 mo of antibody administration at sites initially felt to be falsely positive on scan. One patient developed a human antichimeric antibody response predominantly to the murine portion of the antibody. The antibody cleared serum with a median T(1/2alpha) of 6.53 hr and a T(1/2beta) of 90.87 hr. Interpatient variations in serum clearance rates were observed and were secondary to differences in clearance and metabolic rates of antibody-antigen complexes by the liver. One patient demonstrated very rapid clearance of antibody by the liver, which compromised antibody localization to the primary tumor. Antibody uptake in primary and metastatic tumors ranged from 0.5% to 10.5% injected dose/kg, resulting in estimated radiation doses ranging from 0.97 to 21.3 cGy/mCi 90Y. Antibody uptake in regional lymph nodes ranged from 1.3% to 377% injected dose/kg, resulting in estimated radiation doses ranging from 2.0 to 617 cGy/mCi 90Y.
Chimeric T84.66 demonstrated tumor targeting that was comparable to that of other radiolabeled intact anti-CEA Mabs. Its immunogenicity after single administration was lower than murine Mabs. These properties make cT84.66 or a lower molecular weight derivative attractive for further evaluation as an imaging agent. These same properties also make it appropriate for future evaluation in Phase I therapy trials. Finally, a wide variation in the rate of antibody clearance was observed, with one patient demonstrating very slow clearance, resulting in the highest estimated marrow dose of the group, and one patient demonstrating unusually rapid clearance, resulting in poor antibody localization to tumor. Data from this study suggest that serum CEA levels, antibody-antigen complex clearance and, therefore, antibody clearance are influenced by both the production and clearance rates of CEA. This underscores the need to further identify, characterize and understand those factors that influence the biodistribution and clearance of radiolabeled anti-CEA antibodies to allow for better selection of patients for therapy and rational planning of radioimmunotherapy.
嵌合型T84.66（cT84.66）是一种针对癌胚抗原（CEA）的高亲和力（1.16×10¹¹ M⁻¹）IgG1单克隆抗体（MAb）。该初步试验评估了¹¹¹In标记的cT84.66的肿瘤靶向特性、生物分布、药代动力学和免疫原性。
给产生CEA的转移性恶性肿瘤患者静脉内单次注射5 mCi¹¹¹In-二乙烯三胺五乙酸-cT84.66。在输注后长达7天收集系列血样、24小时尿液收集物和核图像。在输注后长达6个月评估人抗嵌合抗体反应。
15例患者中有14例（93%）观察到至少一个已知肿瘤部位的显像。分析了74个病灶，显像灵敏度率为45.1%，阳性预测值为94.1%。在一名患者中，在抗体给药后6个月内，最初扫描时认为是假阳性的部位出现了另外两处骨转移。一名患者产生了主要针对抗体鼠源部分的人抗嵌合抗体反应。抗体清除血清的中位T(1/2α)为6.53小时，T(1/2β)为90.87小时。观察到患者间血清清除率存在差异，这是由于肝脏对抗体-抗原复合物的清除和代谢率不同所致。一名患者肝脏对抗体的清除非常迅速，这损害了抗体在原发肿瘤的定位。原发肿瘤和转移瘤中的抗体摄取范围为0.5%至10.5%注射剂量/千克，导致估计辐射剂量范围为0.97至21.3 cGy/mCi 90Y。区域淋巴结中的抗体摄取范围为1.3%至377%注射剂量/千克，导致估计辐射剂量范围为2.0至617 cGy/mCi 90Y。
嵌合型T84.66显示出与其他放射性标记的完整抗CEA单克隆抗体相当的肿瘤靶向性。单次给药后的免疫原性低于鼠源单克隆抗体。这些特性使cT84.66或低分子量衍生物作为显像剂具有进一步评估的吸引力。这些相同的特性也使其适合在I期治疗试验中进行未来评估。最后，观察到抗体清除率存在很大差异，一名患者显示清除非常缓慢，导致该组中估计骨髓剂量最高，一名患者显示异常快速清除，导致抗体在肿瘤中的定位不佳。本研究数据表明，血清CEA水平、抗体-抗原复合物清除以及因此抗体清除受CEA的产生和清除率影响。这强调了进一步识别、表征和理解那些影响放射性标记抗CEA抗体生物分布和清除的因素的必要性，以便更好地选择治疗患者并合理规划放射免疫治疗。
