Horak E, Hartmann F, Garmestani K, Wu C, Brechbiel M, Gansow O A, Landolfi N F, Waldmann T A
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Nucl Med. 1997 Dec;38(12):1944-50.
The specificity, toxicity and efficacy of lead (212Pb) radioimmunotherapy were evaluated in nude mice bearing the SK-OV-3 human ovarian tumor cell line expressing the HER2/neu proto-oncogene.
The therapeutic agent used was the tumor-specific anti-HER2/neu monoclonal antibody AE1 conjugated to 212Pb, 212Bi being the daughter and thus the source of the alpha-particle and beta emissions. A bifunctional derivative of tetraazacyclododecanetetraacetic acid (p-SCN-Bz-DOTA) was used to couple 212Pb to the anti-HER2/neu monoclonal antibody AE1. The chelating agent did not alter the binding affinity to its antigenic target or the pharmacokinetics and tissue distribution of the AE1 antibody. Toxicity and therapeutic efficacy of 212Pb-AE1 were evaluated in nude mouse ascites or solid tumor models, wherein SK-OV-3 cells were administered i.p. or s.c., respectively.
The dose-limiting acute toxicity after i.v. administration of 212Pb-AE1 was bone marrow suppression, which was observed at doses above 25 microCi. Therefore, doses of 10 and 20 microCi were used in efficacy trials. The i.p. administration of 212Pb-AE1 3 days after i.p. tumor inoculation led to a significant (P2 = 0.015) prolongation of tumor-free survival. In a second model, i.v. treatment with 212Pb-AE1 3 days after s.c. tumor inoculation prevented subsequent tumor development in all animals treated with 10 or 20 microCi of 212Pb-AE1 (P2 = 0.002 compared to control groups). This efficacy in the adjuvant setting was antibody specific because treatments with equivalently labeled control antibody or unlabeled AE1 antibody or no treatment were less effective. The rate of growth of small (mean tumor volume, 15 mm3) SK-OV-3 tumors was modestly inhibited. However, tumor growth was not inhibited in mice bearing larger (mean tumor volume, 146 mm3) SK-OV-3 tumors by the administration of a single dose of 10 or 20 microCi of 212Pb-AE1.
Lead-212-AE1 as an intact radiolabeled monoclonal antibody may be of only modest value in the therapy of bulky solid tumors due to the short physical half-life of 212Pb and time required to achieve a useful tumor-to-normal tissue ratio of radionuclide after administration. However, the radiolabeled monoclonal antibody may be useful in therapy of tumors in the adjuvant setting. Furthermore, 212Pb may be of value in select situations, including treatment of leukemia, intercavitary therapy or strategies that target vascular endothelial cells of tumors.
在携带表达HER2/neu原癌基因的SK-OV-3人卵巢肿瘤细胞系的裸鼠中评估了铅（²¹²Pb）放射免疫疗法的特异性、毒性和疗效。
所使用的治疗剂是与²¹²Pb偶联的肿瘤特异性抗HER2/neu单克隆抗体AE1，²¹²Bi是子体，因此是α粒子和β发射的来源。使用四氮杂环十二烷四乙酸的双功能衍生物（p-SCN-Bz-DOTA）将²¹²Pb与抗HER2/neu单克隆抗体AE1偶联。螯合剂不会改变其与抗原靶点的结合亲和力或AE1抗体的药代动力学和组织分布。在裸鼠腹水或实体瘤模型中评估²¹²Pb-AE1的毒性和治疗效果，其中SK-OV-3细胞分别通过腹腔注射或皮下注射给药。
静脉注射²¹²Pb-AE1后的剂量限制性急性毒性是骨髓抑制，在剂量高于25微居里时观察到。因此，在疗效试验中使用了10和20微居里的剂量。在腹腔接种肿瘤3天后腹腔注射²¹²Pb-AE1导致无瘤生存期显著延长（P2 = 0.015）。在第二个模型中，在皮下接种肿瘤3天后用²¹²Pb-AE1进行静脉治疗可预防所有接受10或20微居里²¹²Pb-AE1治疗的动物随后发生肿瘤（与对照组相比，P2 = 0.002）。这种在辅助治疗中的疗效是抗体特异性的，因为用等效标记的对照抗体或未标记的AE1抗体治疗或不治疗效果较差。小的（平均肿瘤体积，15立方毫米）SK-OV-3肿瘤的生长速率受到适度抑制。然而，通过单次给予10或20微居里的²¹²Pb-AE1，在携带较大（平均肿瘤体积，146立方毫米）SK-OV-3肿瘤的小鼠中肿瘤生长未受到抑制。
由于²¹²Pb的物理半衰期短以及给药后达到有用的肿瘤与正常组织放射性核素比值所需的时间，作为完整的放射性标记单克隆抗体的铅-212-AE1在治疗大的实体瘤方面可能价值有限。然而，放射性标记单克隆抗体在辅助治疗肿瘤方面可能有用。此外，²¹²Pb在某些情况下可能有价值，包括治疗白血病、腔内治疗或靶向肿瘤血管内皮细胞的策略。
