剖析抗体依赖增强调制通过Fc修饰的交叉中和的人类单克隆抗体
Subenya Injampa1, Surachet Benjathummarak2, Sujitra Keadsanti2
1Faculty of Medicine, King Mongkut's Institute of Technology, Ladkrabang, Bangkok, Thailand.
PeerJ
|November 24, 2025
概括
研究人员开发了一种新的人类单克隆抗体,LALA-B3B9,可以中和所有四种登革热病毒血清型,而不会导致抗体依赖增强 (ADE). 这种抗体通过在体外抑制ADE,对登革热治疗具有前景.
科学领域:
- 免疫学 免疫学 免疫学
- 病毒学 病毒学
- 治疗性抗体的开发方法
背景情况:
- 登革热病毒 (DENV) 感染对全球健康构成重大威胁,由于抗体依赖增强 (ADE),二次感染可能会恶化.
- ADE涉及亚中和抗体,通过激活免疫细胞和补充,增加病毒感染的严重程度.
- 目前的治疗选择,特别是完全人类单克隆抗体,对于登革热缺乏.
研究的目的:
- 开发和描述一种新型的人类单克隆抗体 (HuMAb),能够在不诱导ADE的情况下中和所有四种DENV血清型.
- 在登革热的临床前模型中评估工程HuMAbs,特别是LALA-B3B9的治疗潜力.
- 评估Fc修改对抗体效应器功能和治疗疗效的影响.
主要方法:
- 产生LALA突变的人类单克隆抗体克隆B3B9 (LALA-B3B9 HuMAb).
- 使用ADE测定以不同的抗体度和补充蛋白质来评估中和ADE活动.
- 通过使用K562细胞和患者衍生的抗DENV抗体进行体外抑制增强试验来评估治疗疗效.
主要成果:
- 拉拉-B3B9HuMAb在没有诱导ADE的情况下,对所有四种DENV血清型都表现出强大的中和活性.
- 经Fc修饰的抗体 (LALA-B3B9和N297Q-B3B9) 显示了补充体独立活性,减少C1q结合不影响中和或增强.
- LALA-B3B9和N297Q-B3B9 HuMAbs在体外有效地抑制了由人类抗DENV血清抗体诱导的ADE.
结论:
- 修改Fc的人类单克隆抗体,如LALA-B3B9,有效中和DENV并抑制ADE.
- 这些抗体为预防登革热的被动免疫疗法提供了一个有希望的策略,有可能克服与ADE相关的并发症.
- 这些工程抗体的进一步开发可能会导致登革热的新型治疗干预措施.
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