Zhu H, Jain R K, Baxter L T
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
J Nucl Med. 1998 Jan;39(1):65-76.
The limited success of the sole use of monoclonal antibodies for cancer detection and treatment has led to the development of multistep methods using antibodies in conjunction with low molecular weight agents. For tumor pretargeting, it is important to optimize dose and schedule of relevant agents and to understand barriers to targeted delivery. Here, we address these issues for the anti-carcinoembryonic antigen bifunctional antibody-hapten and the streptavidinylated antibody-biotin systems using a recently developed physiologically based pharmacokinetic model.
For baseline conditions of a standard 70-kg man with a 20-g tumor embedded in the liver, the model was used in conjunction with the Medical Internal Radiation Dosimetry schema to: estimate absorbed doses in tumor and normal tissues; determine the dose dependence of effector agent accumulation in tumor; simulate tumor-to-background effector agent uptake ratio; and calculate the therapeutic ratio for different antibody forms and radionuclides. Alternative drug administration schemes and variable tumor physiological conditions were considered.
Model simulations showed that 131I-labeled biotin with the streptavidinylated F(ab')2 provided the highest therapeutic ratio under the optimized conditions. The simulations also showed that biotin with the bifunctional streptavidinylated immunoglobulin G provided the highest tumor-to-liver uptake ratio during the early period. Sensitivity analysis showed that antibody extravasation was the major factor limiting the accretion of the effector agent in tumor, whereas antigen expression in normal tissues and tumor antigen shedding had little effect on the absorbed doses.
Tumor pretargeting should provide a definite advantage over direct antibody targeting with up to a 200% increase in tumor-to-background ratio in radioimmunodetection and up to a 76% increase in tumor-to-bone marrow therapeutic ratio in radioimmunotherapy. Rapid antibody clearance from the bloodstream before effector agent injection is expected to improve the therapeutic ratio marginally (3%-10%). However, continuous plasmapheresis dramatically increased the tumor-to-background ratio by a factor of 10 in RAID and the tumor-to-bone marrow therapeutic ratio by more than 110% for short-lived radionuclides in RAIT. Apart from drastic measures such as extended plasmapheresis, pretargeting selectivity was neither sensitive enough for radioimmunodetection nor effective enough for radioimmunotherapy in patients with typical solid tumors even using the optimized protocols.
单纯使用单克隆抗体进行癌症检测和治疗的效果有限，这促使人们开发出将抗体与低分子量药物联合使用的多步骤方法。对于肿瘤预靶向治疗而言，优化相关药物的剂量和给药方案以及了解靶向递送的障碍非常重要。在此，我们使用最近开发的基于生理学的药代动力学模型来解决抗癌胚抗原双功能抗体-半抗原和链霉亲和素化抗体-生物素系统的这些问题。
对于一名标准体重70千克、肝脏中有一个20克肿瘤的男性的基线情况，该模型与医学内照射剂量学方案结合使用，以：估计肿瘤和正常组织中的吸收剂量；确定效应剂在肿瘤中积累的剂量依赖性；模拟肿瘤与背景效应剂摄取率；并计算不同抗体形式和放射性核素的治疗比率。考虑了替代给药方案和可变的肿瘤生理状况。
模型模拟表明，在优化条件下，用链霉亲和素化的F(ab')2标记的131I生物素提供了最高的治疗比率。模拟还表明，双功能链霉亲和素化免疫球蛋白G的生物素在早期提供了最高的肿瘤与肝脏摄取率。敏感性分析表明，抗体外渗是限制效应剂在肿瘤中积聚的主要因素，而正常组织中的抗原表达和肿瘤抗原脱落对吸收剂量影响很小。
肿瘤预靶向治疗相对于直接抗体靶向应该具有明显优势，在放射免疫检测中肿瘤与背景比率可提高高达200%，在放射免疫治疗中肿瘤与骨髓治疗比率可提高高达76%。在注射效应剂之前从血液中快速清除抗体预计可使治疗比率略有提高（3%-10%）。然而，连续血浆置换在放射免疫检测中使肿瘤与背景比率显著提高了10倍，在放射免疫治疗中对于短寿命放射性核素使肿瘤与骨髓治疗比率提高了超过110%。除了如延长血浆置换等极端措施外，即使使用优化方案，预靶向选择性对于典型实体瘤患者的放射免疫检测也不够敏感，对于放射免疫治疗也不够有效。
