Buchsbaum D J
Department of Radiation Oncology, University of Alabama at Birmingham 35233, USA.
Cancer Res. 1995 Dec 1;55(23 Suppl):5729s-5732s.
Approaches have been developed to improve the localization of radiolabeled monoclonal antibodies (MAbs) in experimental tumors, to reduce their uptake in normal tissues, and, thus, to improve the time-dependent tumor: normal tissue (T:NT) ratios so that higher and more frequent doses of radionuclide could be used for radioimmunotherapy. These approaches involve three general strategies: (a) modifying antibodies or radiolabeling techniques; (b) increasing the clearance of radiolabeled MAbs; and (c) modifying tumor delivery, tumor antigen expression, or increasing tumor vascular permeability or blood flow. The use of animal models permits the assessment of a wide range of MAbs, radiolabeling conditions, and the efficacy of administration methods before their initial use in clinical trials. MAbs with specificity for binding to tumor-associated antigens or growth factor receptors expressed on tumor cells have been utilized in experimental studies of radiolabeled antibody targeting. Tumor-associated targets present on endothelial cells should be highly accessible to systemically administered radiolabeled MAbs. The use of indirect radio-iodination techniques and labile linker-chelates may provide an improvement in tumor retention and T:NT ratios. The addition or deletion of glycosylation to MAbs by alteration of recombinant immunoglobulin genes or by biochemical modification can alter the pharmacokinetics of blood and whole body clearance of radiolabeled MAbs. Genetically engineered chimeric or humanized MAbs have shown equivalent or greater tumor localization compared to murine MAbs. By using MAbs with greater affinity and avidity, an increase in the uptake and retention of radiolabeled MAbs in tumors and an increase in their therapeutic efficacy may be achieved. Several approaches in the administration methods of MAbs have been developed in an attempt to improve tumor localization and therapeutic results and to reduce toxicity. These approaches include: (a) predosing with unlabeled antibody before administering a radiolabeled MAb; (b) using a mixture or "cocktail" of MAbs rather than a single radiolabeled antibody; and (c) administering multiple doses of radiolabeled MAbs. Various approaches have been tested for increasing the blood clearance of radiolabeled MAbs and, thus, for increasing the T:NT ratio. It has been found that compared to intact antibody, the smaller antibody fragments (F(ab')2, Fab, or single-chain Fv) can bind to tumor cells with a more homogeneous distribution. The antibody fragments and domain deletions often have a more rapid catabolism in blood, in tumors, and in normal tissues than an intact antibody does. In general, the use of antibody fragments leads to higher T:NT ratios but a lower percentage of injected dose delivered to the tumor.
已经开发出多种方法来改善放射性标记单克隆抗体（MAb）在实验性肿瘤中的定位，减少其在正常组织中的摄取，从而提高时间依赖性肿瘤与正常组织（T:NT）的比值，以便能够使用更高且更频繁剂量的放射性核素进行放射免疫治疗。这些方法涉及三种一般策略：（a）修饰抗体或放射性标记技术；（b）增加放射性标记MAb的清除率；（c）修饰肿瘤递送、肿瘤抗原表达，或增加肿瘤血管通透性或血流量。动物模型的使用使得在首次用于临床试验之前，可以评估多种MAb、放射性标记条件以及给药方法的疗效。对肿瘤细胞上表达的肿瘤相关抗原或生长因子受体具有特异性结合能力的MAb已被用于放射性标记抗体靶向的实验研究。内皮细胞上存在的肿瘤相关靶点应该易于被全身给药的放射性标记MAb所识别。使用间接放射性碘化技术和不稳定的连接体螯合物可能会改善肿瘤滞留和T:NT比值。通过改变重组免疫球蛋白基因或进行生化修饰对MAb进行糖基化的添加或缺失，可以改变放射性标记MAb在血液中的药代动力学和全身清除率。与鼠源MAb相比，基因工程嵌合或人源化MAb显示出同等或更高的肿瘤定位。通过使用具有更高亲和力和avidity的MAb，可以实现放射性标记MAb在肿瘤中的摄取和滞留增加以及其治疗效果提高。已经开发出几种MAb给药方法，试图改善肿瘤定位和治疗效果并降低毒性。这些方法包括：（a）在给予放射性标记MAb之前预先给予未标记的抗体；（b）使用MAb混合物或“鸡尾酒”而不是单一的放射性标记抗体；（c）给予多剂量的放射性标记MAb。已经测试了各种方法来增加放射性标记MAb的血液清除率，从而提高T:NT比值。已经发现，与完整抗体相比，较小的抗体片段（F(ab')2、Fab或单链Fv）能够以更均匀的分布与肿瘤细胞结合。抗体片段和结构域缺失在血液、肿瘤和正常组织中的分解代谢通常比完整抗体更快。一般来说，使用抗体片段会导致更高的T:NT比值，但递送至肿瘤的注射剂量百分比更低。
