Pharmacokinetics and ibmor localization of 111In-labeled HuCC49ΔCH2 in BALB/c mice and athymic murine colon carcinoma xenograft
Pharmacokinetics and ibmor localization of 111In-labeled HuCC49ΔCH2 in BALB/c mice and athymic murine colon carcinoma xenograft
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DOI：
10.1089/cbr.2006.21.106
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发表时间：
2006-04-01
影响因子：
3.4
通讯作者：
Braslawsky, Gary
中科院分区：
文献类型：
--
作者：
Chinn, Paul C.;Morena, Ron A.;Braslawsky, Gary
IgG 抗体用于实体瘤放射免疫治疗的主要限制是其血清半衰期延长，在向肿瘤提供不充分辐射的剂量下会导致剂量限制性骨髓毒性。与 IgG 相比，抗 TAG-72 抗体 CC49 (HuCC49 Delta C(H)2) 的人源化 C(H)2 结构域缺失变体具有更快的血液清除率，同时保留肿瘤靶向性。我们比较了 BALE/c 小鼠和结肠癌 (LS-174T) 小鼠异种移植物中 In-111-HuCC49 Delta C(H)2 的药代动力学和肿瘤摄取与 In-111 标记的嵌合 CC49 (cCC49) 的药代动力学和肿瘤摄取，后者是一种药代动力学与人源化 CC49 亲本相似的抗体。 使用 In-111 螯合剂 Mx-DTPA（1-异硫氰基苄基-3-甲基二亚乙基三胺五乙酸）制备的 HuCC49 Delta C(H)2 和 cCC49 保留了低 nM 亲和力，放射性标记方案提供了大于 95% 的 In-111 放射性掺入，同时保留大于 80% 的免疫反应性。 BALB/c 小鼠中 In-111-HuCC49 Delta C(H)2 的血液清除率为单指数（t(1/2) 5.4 小时），并且比 In-111-cCC49 更快（双指数清除；t(1/2 α) 1.5 小时；t(1/2 β) 162 小时）。 In-111-HuCC49 Delta C(H)2 也能更快地从小鼠异种移植物的血液中清除。注射后 1 小时，In-111-HuCC49 Delta C(H)2 和 In-111-cCC49 的血液浓度相当（分别为 25.5 注射剂量/g [%ID/g] 和 21.3 %ID/g）； tumor uptake for (111)InHuCC49 Delta C(H)2 was 7.9 %ID/g, compared to 7.5 %ID/g for In-111-cCC49.然而，在 24 小时时，In-111-HuCC49 Delta C(H)2 的血液浓度低于 In-111-cCC49（分别为 0.9%ID/g 与 5.2%ID/g），而肿瘤保留率相当（分别为 14.4%ID/g 与 19.0%ID/g）。 In-111-HuCC49 Delta C(H)2 更快的血液清除率和肿瘤定位与 In-111-cCC49 相当，注射后 24 小时，In-111-HuCC49 Delta C(H)2 的肿瘤与血液比率提高了四倍。
The primary limitation of IgG antibodies for radioimmunotherapy of solid tumors is their prolonged serum half-life, leading to dose-limiting bone marrow toxicity at doses providing inadequate radiation to the tumor. A humanized C(H)2 domain-deleted variant of the anti-TAG-72 antibody CC49 (HuCC49 Delta C(H)2) has faster blood clearance, compared to the IgG, while retaining tumor targeting. We compared the pharmacokinetics and tumor uptake of In-111-HuCC49 Delta C(H)2 in BALE/c mice and a colon carcinoma (LS-174T) mouse xenograft with that of In-111-labeled chimeric CC49 (cCC49), an antibody with pharmacokinetics similar to the humanized CC49 parent., Immunoconjugates of HuCC49 Delta C(H)2 and cCC49 prepared with the In-111 chelator Mx-DTPA (1-isothiocyantobenzyl-3-methyldiethylenetriaminepentaacetic acid) retained low nM affinity and radiolabeling protocols provided greater than 95% radioincorporation with In-111 while retaining greater than 80% immunoreactivity. Blood clearance of In-111-HuCC49 Delta C(H)2 in BALB/c mice was monoexponential (t(1/2) 5.4 hours) and faster than In-111-cCC49 (biexponential clearance; t(1/2 alpha) 1.5 hours; t(1/2 beta) 162 hours). The In-111-HuCC49 Delta C(H)2 also cleared more rapidly from the blood in the murine xenograft. At 1 hour postinjection, blood concentrations for In-111-HuCC49 Delta C(H)2 and In-111-cCC49 were comparable (25.5 injected dose per g [%ID/g] and 21.3 %ID/g, respectively); tumor uptake for (111)InHuCC49 Delta C(H)2 was 7.9 %ID/g, compared to 7.5 %ID/g for In-111-cCC49. However, at 24 hours, blood concentration for In-111-HuCC49 Delta C(H)2 was less than In-111-cCC49 (0.9 %ID/g versus 5.2 %ID/g, respectively) with comparable tumor retention (14.4 %ID/g versus 19.0 %ID/g, respectively). Faster blood clearance of In-111-HuCC49 Delta C(H)2 and tumor localization comparable to that of In-111-cCC49 provided a fourfold improved tumor-to-blood ratio for In-111-HuCC49 Delta C(H)2 at 24 hours postinjection.