DeNardo Gerald L, DeNardo Sally J
Department of Internal Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA.
Cancer Biother Radiopharm. 2004 Feb;19(1):85-92. doi: 10.1089/108497804773391720.
Radioimmunotherapy (RIT) delivered by radiometal immunoconjugates (RICs) is dose limited by deposition and retention of radioactivity in normal tissues. In order to increase elimination of radioactivity from the liver and body, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate, 111In-DOTA, and the panadenocarcinoma monoclonal antibody (MAb), m170.
Indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-2-iminothiolane (2IT)-m170 and 111In-DOTA-peptide-m170, representing the same MAb and chelate without and with a cleavable linkage, were studied in athymic mice and patients with breast or prostate cancer. Pharmacokinetics, cumulated activities and therapeutic indices (TI), were evaluated. Cumulated activities in the liver and tumors were calculated and used as a surrogate for radiation dose.
Except for liver, the pharmacokinetics of 111In-DOTA-peptide-m170 were similar to those of the 111In-2IT-2-[p(bromoacetamido)benzyl]-1,4,7,10-tetraazocyclododecane-N,N',N",N"'-tetraacetic acid-m170 (111In-2IT-BAD-m170) in mice and patients. Liver cumulated activities for 111In-DOTA-peptide-m170 were consistently decreased when compared to those for 111In-2IT-BAD-m170, reductions varying between 22-30%. Cumulated activities for 111In-DOTA-peptide-m170 in the malignant tumors of the patients were as great as those for 111In-2IT-BAD-m170, so that the tumor-to-liver cumulated activity ratios (therapeutic indices) were better for 111In-DOTA-peptide-m170.
A cathepsin-B-cleavable peptide used to link chelated 111In to MAb, m170, reduced liver cumulated activity (radiation dose) and improved the TI. This novel linker illustrates the importance of linker technology in the development of safer RICs for cancer therapy.
放射性金属免疫偶联物（RICs）介导的放射免疫疗法（RIT）的剂量受到放射性在正常组织中的沉积和滞留的限制。为了增加肝脏和体内放射性的消除，在放射性金属螯合物111In-DOTA与泛腺癌单克隆抗体（MAb）m170之间引入了一个具有组织蛋白酶B特异性切割位点的肽段。
在无胸腺小鼠以及乳腺癌或前列腺癌患者中研究了铟-111（111In）-1,4,7,10-四氮杂环十二烷-N,N',N",N"'-四乙酸（DOTA）-2-亚氨基硫醇（2IT）-m170和111In-DOTA-肽-m170，后者代表相同的单克隆抗体和螯合物，但分别有无可切割连接子。评估了药代动力学、累积活度和治疗指数（TI）。计算肝脏和肿瘤中的累积活度，并将其用作辐射剂量的替代指标。
除肝脏外，111In-DOTA-肽-m170在小鼠和患者中的药代动力学与111In-2IT-2-[对（溴乙酰胺基）苄基]-1,4,7,10-四氮杂环十二烷-N,N',N",N"'-四乙酸-m170（111In-2IT-BAD-m170）相似。与111In-2IT-BAD-m170相比，111In-DOTA-肽-m170的肝脏累积活度持续降低，降低幅度在22%至30%之间。患者恶性肿瘤中111In-DOTA-肽-m170的累积活度与111In-2IT-BAD-m170相当，因此111In-DOTA-肽-m170的肿瘤与肝脏累积活度比（治疗指数）更高。
用于将螯合的111In与单克隆抗体m170连接的组织蛋白酶B可切割肽降低了肝脏累积活度（辐射剂量）并改善了治疗指数。这种新型连接子说明了连接子技术在开发更安全的用于癌症治疗的RICs中的重要性。
