治疗性抗体评估服务
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JAX 治疗性抗体评估服务利用了独特的人源化小鼠。我们的人源化 FcRn 模型可以提供准确的数据,缩短候选治疗药物进入临床所需的时间,并最终将药物交给医生和患者本人。

相关讲座

 
《人源化FcRn小鼠加速赋能新型抗体DMPK精准分析》

立即观看

 

 

从临床前到临床:获得相关的转化和快速的半衰期比较数据

我们借助自身独有的平台(由缺乏鼠 FcRn 并以不同水平表达人 FcRn 的人源化小鼠模型组成)评估治疗性抗体和其他基于 Fc 的生物制剂的体内稳定性。这些小鼠由 来自JAX 的Derry Roopenian教授构建,具有以下优势

  • 产生更快、可预测的与临床相关的抗体稳定性数据,
  • 一种有效且已被证实的非人灵长类动物替代,
  • 基于 Fc 结构域的候选治疗药物的临床前药代动力学 (PK) 分析,
  • 性价比高,只需要少量的特定分子,
  • 测试用于免疫肿瘤学和自身免疫研究的各种 Fc 结构域白蛋白融合药物或采用了白蛋白的治疗方法等

 

临床前模型的药代动力学临床相关性

模型 成本 与人体数据的相关性
体外
普通小鼠 中度
人源化 FcRn 小鼠 中度 极高
非人灵长类动物 极高

 

人源化小鼠平台: 常用模型

B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) 小鼠具有靶向突变导致的基因缺失,且存在一个在内源性启动子 (hTg32) 驱动下表达的人 FcRn 的转基因。这些小鼠对人源化 IgG 抗体具有高效和类似人类的保护作用,是在需要最大半衰期数据时使用的最佳模型。

 

B6.Cg-Fcgrttm1Dcr Tg(CAG-FCGRT)276Dcr/DcrJ (004919) 小鼠具有靶向突变导致的基因缺失和表达人 FcRn 的转基因。 人 FcRn 转基因 (hTg276) 的半合子小鼠适合检测体内抗体持久性的细微差异。

 

B6.Cg-Fcgrttm1Dcr Prkdcscid Tg(FCGRT)32Dcr/DcrJ (018441) 小鼠表达 hTg32 转基因,同时免疫缺陷。这些小鼠对人源化 IgG 具有高效和类似人类的保护作用,可用于评价具有潜在免疫原性或涉及异种移植物的基于 Fc 结构域的治疗药物。

 

B6.Cg-Albem12Mvw  Fcgrttm1Dcr Tg(FCGRT)32Dcr/MvwJ (025201) 白蛋白敲除 hTg32 小鼠是一种有效的类人模型,可用于表征白蛋白融合药物或基于白蛋白的疗法的药代动力学。

 

 

FcRn 人源化小鼠模型
 
模型 内源性启动子 最长的半衰期 评价 PK 值的细微差异 免疫缺陷 白蛋白 PK

FcRn Tg32 (014565)

FcRn Tg276 (004919)

Tg32 Scid (018441)

Tg276 Scid* (021146)

Tg276 Rag1* (016919)

Tg32 Alb KO (025201

否 

*需冷冻复苏

 

 

研究示例

 

药代动力学研究设计示例

注: 所有研究均按照客户要求设计

  • 一项使用了 6 只 B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) 小鼠的标准研究。
  • 实验药物及空白对照均通过 IV(静脉注射)给药。
  • 实验药物经 IV 给药后 1、2、6、10、14、18、22 和 26 天采集血样。
  • 通过 ELISA 定量分析实验药物的浓度,并使用 PK Solutions 软件计算药代动力学数据。

 

 药效学研究设计示例

 注: 所有研究均按照客户要求设计

  • 一项使用了 6 只 B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) 小鼠的标准研究。
  • 通过 IV 给予小鼠人 IgG,24 小时后采集血样。
  • 采血后 1 小时,通过 IV 给予实验药物和空白对照。
  • 32、48、56、72、96、120 和 144 小时后采集血样。
  • 通过 ELISA 定量分析人 IgG 或白蛋白的浓度,并使用 PK Solutions 软件计算药效学数据。

 

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Low BE, Wiles MV. 2016. A Humanized Mouse Model to Study Human Albumin and Albumin Conjugates Pharmacokinetics. Methods Mol Biol. 1438:115-22. PMID: 27150087

 

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