Behr T M, Goldenberg D M, Becker W
Department of Nuclear Medicine, Georg-August-University of Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany.
Eur J Nucl Med. 1998 Feb;25(2):201-12. doi: 10.1007/s002590050216.
Elevated renal uptake and prolonged retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. Over recent years, one of the focuses of research has therefore been to develop suitable methods to reduce this renal uptake, and to evaluate whether the resulting methodology will benefit therapy with antibody fragments and peptides. In these studies it has been shown that the kidney uptake of antibody fragments in animals can be reduced in a dose-dependent manner by almost one order of magnitude by the systemic administration of cationic amino acids and their derivatives, whereas the uptake in all other organs, as well as the tumor, remains unaffected. A similar reduction in renal retention is achieved for all intracellularly retained radionuclides (e.g., radiometals) or radioiodinated immunoconjugates, as well as for smaller peptides. Lysine is usually the preferred agent, and its d- and l-isomers are equally effective whether given intraperitoneally or orally. Amino sugars are effective, but their N-acetyl derivatives, lacking the positive charge, are not. Basic polypeptides are also effective, and their potency increases with increasing molecular weight (i.e., the amount of positive charges per molecule). Urine analysis of treated individuals shows the excretion of unmetabolized, intact fragments or peptides, in contrast to mostly low-molecular-weight metabolites in untreated controls. In therapy studies using radiometal-conjugated Fab fragments, the kidney is the first dose-limiting organ. Administration of cationic amino acids results in a substantial increase in the maximum tolerated dose of such Fab fragments. No biochemical or histological evidence of renal damage has been observed under these conditions. As was the case in animal studies, in pilot clinical trials the renal uptake in patients injected with Fab' fragments and given amino acids could be decreased significantly, whereas the uptake by all other organs remained unaffected. These recent studies indicate that a variety of basic compounds are capable of inhibiting the tubular reabsorption of peptides and proteins, thus significantly lowering the renal uptake of antibody fragments or peptides in both animals and patients. On a molecular basis, the effect seems to rely essentially on the presence of a positively charged amino group. Thus, radiation nephrotoxicity of antibody fragments and peptides can be overcome successfully; this may provide new prospects for cancer therapy with radiolabeled antibody fragments and peptides.
放射性标记的抗体片段和肽在肾脏的摄取增加以及滞留时间延长是这类药物治疗应用中的一个问题。因此，近年来研究的重点之一是开发合适的方法来减少这种肾脏摄取，并评估所产生的方法是否会有益于抗体片段和肽的治疗。在这些研究中已经表明，通过全身给予阳离子氨基酸及其衍生物，动物体内抗体片段的肾脏摄取可以以剂量依赖的方式降低近一个数量级，而所有其他器官以及肿瘤中的摄取不受影响。对于所有细胞内滞留的放射性核素（例如放射性金属）或放射性碘化免疫缀合物以及较小的肽，肾脏滞留也有类似程度的降低。赖氨酸通常是首选药物，其d-和l-异构体无论是腹腔内给药还是口服给药，效果均相同。氨基糖是有效的，但其缺乏正电荷的N-乙酰基衍生物则无效。碱性多肽也是有效的，并且它们的效力随着分子量的增加（即每个分子的正电荷数量）而增加。对接受治疗的个体进行尿液分析显示，排出的是未代谢的完整片段或肽，这与未治疗的对照组中大多为低分子量代谢产物形成对比。在使用放射性金属缀合的Fab片段的治疗研究中，肾脏是第一个剂量限制器官。给予阳离子氨基酸会导致此类Fab片段的最大耐受剂量大幅增加。在这些条件下未观察到肾脏损伤的生化或组织学证据。与动物研究的情况一样，在初步临床试验中，注射Fab'片段并给予氨基酸的患者的肾脏摄取可以显著降低，而所有其他器官的摄取不受影响。这些最新研究表明，多种碱性化合物能够抑制肽和蛋白质的肾小管重吸收，从而显著降低动物和患者体内抗体片段或肽的肾脏摄取。从分子层面来看，这种作用似乎主要依赖于带正电荷的氨基的存在。因此，抗体片段和肽的放射性肾毒性可以成功克服；这可能为用放射性标记的抗体片段和肽进行癌症治疗提供新的前景。
