Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers.
Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers.
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DOI：
10.1186/s13550-016-0180-0
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发表时间：
2016-12
期刊：
影响因子：
3.2
通讯作者：
Scott AM
中科院分区：
文献类型：
--
作者：
Burvenich IJ;Lee FT;O'Keefe GJ;Makris D;Cao D;Gong S;Rigopoulos A;Allan LC;Brechbiel MW;Liu Z;Ramsland PA;Scott AM
这项研究的目的是探索人源化抗Lewis-Y抗体(IgG1)hu3S193的Fc突变，作为一种改善治疗有效载荷输送的治疗比率的策略。通过定点突变产生了四个hu3S193变异体(I253A、H310A、H435A和I253A/H310A)，并用诊断同位素碘-125或铟-111进行放射性标记。在Lewis-Y阳性荷瘤小鼠体内的生物分布研究被用来计算治疗性同位素(碘-131、Y-90和钚-177)在肿瘤和器官中的剂量。111In标记的I253A和H435A表现出相似的缓慢动力学(T1/2β，分别为63.2和62.2h)，最大肿瘤摄取分别为33.11 ± 4.05和33.69 ± 3.77%/克注射剂量(%ID/g)。111In标记的I253A/H310A清除最快(T1/2β，9.1h)，肿瘤最大摄取最低(23.72 ± 0.85%ID/g)。金属标记突变体(90Y和177Lu)的肿瘤与血液曲线下面积(AUC)比率的增加幅度最大。177Lu-CHX-A“DTPA-hu3S193 I253A/H310A(6：1)显示了与野生型(3：1)和其他变种相比最高的肿瘤与血液的AUC比率，以及基于红骨髓剂量限制计算的肿瘤剂量翻倍。这些结果表明，hu3S193 FC可以被设计成提高基于90Y和177Lu的治疗的治疗比率，对于基于177Lu的治疗，最佳候选者是hu3S193 I253A/H310A。本文的在线版本(DOI：10.1186/s13550-016-0180-0)包含补充材料，可供授权用户使用。
The aim of the study was to explore Fc mutations of a humanised anti-Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. Four hu3S193 variants (I253A, H310A, H435A and I253A/H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes iodine-125 or indium-111. Biodistribution studies in Lewis-Y-positive tumour-bearing mice were used to calculate the dose in tumours and organs for therapeutic isotopes (iodine-131, yttrium-90 and lutetium-177). 111In-labelled I253A and H435A showed similar slow kinetics (t1/2β, 63.2 and 62.2 h, respectively) and a maximum tumour uptake of 33.11 ± 4.05 and 33.69 ± 3.77 percentage injected dose per gramme (%ID/g), respectively. 111In-labelled I253A/H310A cleared fastest (t1/2β, 9.1 h) with the lowest maximum tumour uptake (23.72 ± 0.85 %ID/g). The highest increase in tumour-to-blood area under the curve (AUC) ratio was observed with the metal-labelled mutants (90Y and 177Lu). 177Lu-CHX-A" DTPA-hu3S193 I253A/H310A (6:1) showed the highest tumour-to-blood AUC ratio compared to wild type (3:1) and other variants and doubling of calculated dose to tumour based on red marrow dose constraints. These results suggest that hu3S193 Fc can be engineered with improved therapeutic ratios for 90Y- and 177Lu-based therapy, with the best candidate being hu3S193 I253A/H310A for 177Lu-based therapy. The online version of this article (doi:10.1186/s13550-016-0180-0) contains supplementary material, which is available to authorized users.