在体内mRNA表达的多机制的mAb组合可以防止Staphylococcus aureus感染
Christine Tkaczyk1, Michael Newton2, Mun Mun Patnaik1
1AstraZeneca, Early Vaccines & Immune Therapies, Gaithersburg, MD 20878, USA.
概括
传递信使RNA (mRNA) 能够使单克隆抗体 (mAb) 组合在体内表达,克服治疗性抗体开发的可变链错配等挑战.
科学领域:
- 生物技术是生物技术.
- 免疫学 免疫学 免疫学
- 药理学 药理学是指药理学的学科.
背景情况:
- 单个单克隆抗体 (mAbs) 可以通过由脂质纳米粒子 (LNPs) 传递的mRNA在体内表达.
- 同时提供多个mAbs带来了挑战,主要是重型和轻型变量链错配对的风险,可能会影响疗效.
研究的目的:
- 评估通过mRNA/LNP传递的三mAb组合对金黄色葡萄球菌的药理动力学和功能性.
- 评估链错配的可能性及其对单链可变片段 (scFv-Fc) 和免疫球蛋白G1 (IgG1) 格式中中和活性的影响.
主要方法:
- 编码三个mAbs的mRNA对黄金葡萄球菌进行编制,并与LNP配合,用于小鼠和非人类灵长类动物的静脉输送.
- 评估了药理动力学,功能性抗体表达,同源链配对和中和活性.
- 在小鼠模型中评估了有效性,这种小鼠模型是 Staphylococcus aureus 诱导的皮肤病变.
主要成果:
- 静脉注射的mRNA/LNP输送在24小时内诱导了功能性抗体表达,在小鼠3天后,64%-78%的同系链配对IgG表达.
- 在scFv-Fc格式中观察到没有非同类链对的缺失.
- 中和活性仍然与链配对的mAbs的表达水平相似,mAb组合在皮肤缩模型中保护了小鼠.
- 在非人类灵长类动物中,血清IgG峰值水平在2.9~13.7μg/mL之间,半衰期为11.8~15.4天.
结论:
- mAb组合的核酸输送是治疗性抗体开发的有希望的策略.
- 这种方法可以通过减轻与传统的mAb组合交付相关的挑战来简化开发过程.
关键词:
黄金葡萄球菌黄金葡萄球菌阿尔法毒素是一种毒素.细菌的病原发生 细菌的病原发生聚合因子A 聚合因子A免疫疗法 免疫疗法在体内表达的单克隆抗体.在 mRNA/LNP 中.一个单克隆抗体组合.鼠标疾病模型 鼠标疾病模型scFv-Fcc 的意思更多相关视频
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