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 | 低 | 低 |
| 普通小鼠 | 中度 | 低 |
| 人源化 FcRn 小鼠 | 中度 | 极高 |
| 非人灵长类动物 | 高 | 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。
| 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) |
是 | 是 | 否 | 否 | 否 |
|
FcRn Tg276 (004919) |
否 | 否 | 是 | 否 | 否 |
|
Tg32 Scid (018441) |
是 | 是 | 否 | 是 | 否 |
|
Tg276 Scid* (021146) |
否 | 否 | 是 | 是 | 否 |
|
Tg276 Rag1* (016919) |
否 | 否 | 是 | 是 | 否 |
|
Tg32 Alb KO (025201) |
是 | 是 | 否 | 否 | 是 |
*需冷冻复苏
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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