huHSC-NCG小鼠是将人造血干细胞 (CD34+HSC）移植到辐照清髓的重度免疫缺陷小鼠NCG体内，并分化产生各类造血或者免疫细胞，如T细胞、B细胞以及NK细胞等，从而获得免疫系统人源化的模型以NCG小鼠为受体鼠，构建huHSC-NCG人源化小鼠。

应用领域

1. 多种肿瘤免疫治疗药物的评价

2. 免疫相关的药物评价

模型数据

图1. NCG小鼠清髓效果检测

由于辐照可以清除小鼠骨髓中的造血干细胞，从而提高人源HSC移植后的重建水平，因此选用辐照处理后的NCG小鼠移植人源HSC。利用流式细胞技术检测辐照清髓效果。其中mCD45为小鼠白细胞标记物，mCD117为造血干细胞标记物。上图显示辐照后mCD45+mCD117+细胞群体比例为1.11%,显著低于未辐照组（13.5%）。表明150 cGys剂量辐照6-7周NCG小鼠可达到理想的清髓效果。

图2. huHSC-NCG小鼠的生存曲线及体重变化情况

huHSC-NCG小鼠存活时间可超过37周，且生存率与NCG野生型小鼠无显著差异。huHSC-NCG小鼠体重随时间变化呈增长趋势，前期与NCG野生型小鼠体重无显著差异，随着时间延长，huHSC-NCG小鼠体重下降，在实验终点，huHSC-NCG小鼠体重显著低于NCG野生小鼠（***, P < 0.001）。数据以Mean ± SEM形式呈现。

图3. huHSC-NCG重建效果鉴定

huHSC-NCG小鼠的免疫重建效率高，主要重建T细胞和大量未成熟的B细胞，以及少量NK细胞。

图4. 基于huHSC-NCG小鼠模型的体内药效评价

基于huHSC-NCG小鼠体内用药试验。将对数生长期人淋巴瘤细胞Raji细胞接种到huHSC-NCG小鼠皮下，待肿瘤生长至平均体积约40-50 mm3时，根据小鼠肿瘤体积和体重，随机分为Vehicle组，Tri-TE给药组，Blincyto给药组，并使用相应的药物进行治疗。结果显示：Tri-TE组（TGI=62.04%）及Blincyto给药组（TGI=51.14%）对huHSC-NCG的Raji细胞荷瘤鼠上肿瘤生长有抑制作用。

NCG在CAR-T治疗上的应用

CAR-T（Chimeric Antigen Receptor T Cell）是肿瘤免疫治疗的新方法。CAR-T细胞具有靶向识别肿瘤抗原的能力，其杀伤肿瘤细胞无需进行抗原递呈，与以往免疫疗法相比，具有特异性高、攻击持久等优势。在恶性肿瘤，特别是血液肿瘤治疗中有很好的疗效。集萃药康具有丰富的CDX和自主知识产权的PDX库，包括多种实体瘤和血液瘤，为CAR-T药效评价提供了丰富的肿瘤模型资源。同时，集萃药康开发了外周血中CAR-T细胞计数方法和细胞因子检测方法，满足CAR-T实验检测需求。

图5.在NCG小鼠上接种Nalm6-Luciferase后，进行CAR-T药效评价

Nalm6-Luciferase细胞尾静脉接种到NCG小鼠后，第7天根据肿瘤负荷进行分组，分别给予Control T，CAR-T1及CAR-T2细胞治疗，并于D12，D19，D26利用活体成像技术检测肿瘤负荷。据体内成像及统计结果显示，与Control T相比，CAR-T1和CAR-T2细胞均能很好的抑制小鼠体内肿瘤生长，延长小鼠生存期。

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