Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the α-emitting radioisotope astatine-211 conjugated to anti-HER2/neu diabodies
Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the α-emitting radioisotope astatine-211 conjugated to anti-HER2/neu diabodies
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DOI：
10.1158/1078-0432.ccr-07-1250
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发表时间：
2008-02-01
影响因子：
11.5
通讯作者：
Adams, Gregory P.
中科院分区：
文献类型：
--
作者：
Robinson, Matthew K.;Shaller, Calvin;Adams, Gregory P.
目的：成功的放射免疫治疗策略取决于选择具有与靶向载体的生物学性质互补的物理性质的放射性同位素。小的工程化抗肿瘤抗体片段能够在免疫缺陷小鼠模型中快速、高度特异性地靶向肿瘤。我们假设C6.5双抗体，一种非共价抗HER 2单链Fv二聚体，将是使用短寿命α-发射放射性同位素At-211对已建立的肿瘤进行放射免疫治疗的理想放射性同位素载体。用N-琥珀酰亚胺基-N-丁二酰亚胺处理的具有已建立的HER 2/neu阳性MDA-MB-361/DYT 2肿瘤的免疫缺陷裸鼠。（4-[At-211]astatophenethyl）succinamate（At-211-SAPS）-C6.5双抗体。用靶向癌胚抗原的At-211-SAPS T84.66双抗体或对苗勒管抑制物质II型受体特异性的双抗体上的At-211-SAPS处理另外的小鼠群，所述苗勒管抑制物质II型受体在该肿瘤细胞系上最低限度地表达。当施用20 μ Ci剂量时，单次静脉注射At-211-SAPS C6.5双抗体导致肿瘤生长延迟30天，并且导致肿瘤生长延迟57天（1年后60%无肿瘤）。用相同剂量的At-211-SAPS T84.66双抗体治疗携带相同肿瘤的小鼠导致肿瘤生长延迟，但没有完全应答，这可能是由于该抗原在MDA-MB-361/DYT 2肿瘤上的显著较低表达。相比之下，剂量为20 μ Ci的在-211-SAPS的抗苗勒管抑制物质II型受体双抗体并没有影响肿瘤的生长率，表现出特异性的治疗efficence.Conclusions：这些研究结果表明，双抗体分子可以是有效的代理人，有针对性的放射免疫治疗的实体瘤使用强大的，短寿命的α-发射放射性同位素。
Purpose: Successful radioimmunotherapy strategies depend on selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle. Small, engineered antitumor antibody fragments are capable of rapid, highly specific tumor targeting in immunodeficient mouse models. We hypothesized that the C6.5 diabody, a noncovalent anti-HER2 single-chain Fv dimer, would be an ideal radioisotope carrier for the radioimmunotherapy of established tumors using the short-lived a-emitting radioisotope At-211.Experimental Design: Immunodeficient nude mice bearing established HER2/neu-positive MDA-MB-361/DYT2 tumors treated with N-succinimidyl N-(4-[At-211]astatophenethyl)succinamate (At-211-SAPS)-C6.5 diabody. Additional cohorts of mice were treated with At-211-SAPS T84.66 diabody targeting the carcinoembryonic antigen or At-211-SAPS on a diabody specific for the Mullerian inhibiting substance type II receptor, which is minimally expressed on this tumor cell line.Results: A single i.v. injection of At-211-SAPS C6.5 diabody led to a 30-day delay in tumor growth when a 20 mu Ci dose was administered and a 57-day delay in tumor growth (60% tumor-free after 1 year) when a 45 mu Ci dose was used. Treatment of mice bearing the same tumors with At-211-SAPS T84.66 diabody at the same doses led to a delay in tumor growth, but no complete responses, likely due to substantially lower expression of this antigen on the MDA-MB-361/DYT2 tumors. In contrast, a dose of 20 mu Ci of At-211-SAPS on the anti-Mullerian-inhibiting substance type II receptor diabody did not affect tumor growth rate, demonstrating specificity of the therapeutic effect.Conclusions: These findings indicate that diabody molecules can be effective agents for targeted radioimmunotherapy of solid tumors using powerful, short-lived alpha-emitting radioisotopes.