抗体效应器功能的可逆化学修饰减轻了不需要的系统性免疫激活
Philip N Moquist1, Xinqun Zhang2, Chris I Leiske2
1ADC Chemistry, Pfizer, Inc., 21823 30th Dr. SE, Bothell, Washington 98021, United states.
Bioconjugate chemistry
|May 24, 2024
概括
一种新的化学方法可逆调节抗体Fc-Fcγ受体相互作用,减少系统性免疫激活,同时保持抗瘤疗效. 这种方法平衡了强大的治疗效果与提高免疫瘤治疗的安全性.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 生物化学 生物化学
背景情况:
- 像ADCC和ADCP这样的抗体效应器功能依赖于免疫细胞上的Fcγ受体与Fcγ受体的Fc区域相互作用.
- 目前用于增强Fc-Fcγ参与抗瘤反应的方法可以导致全身细胞因子释放和输液反应.
- 在抗体治疗中,平衡强大的抗瘤活性与减少的全身免疫激活是抗体治疗的关键挑战.
研究的目的:
- 开发一种可逆化学调制抗体-Fcγ相互作用的方法.
- 创建一个系统,暂时静止Fcγ参与,并随着时间的推移在体内恢复它.
- 将这项技术应用于增强的CD40抗体 (SEA-CD40) 并评估其安全性和有效性.
主要方法:
- 使用的聚乙烯甘醇 (PEG) 连接剂通过maleimide附着物与抗体间链二硫化物结合.
- 开发了针对抗体Fc-Fcγ相互作用的可逆化学调制策略.
- 在体外和体内测试了这种技术在效应器功能增强激素CD40抗体 (SEA-CD40) 上.
主要成果:
- 在试验室和临床前模型 (小鼠,非人类灵长类动物) 中,Fc诱导的免疫激活显著减少.
- 与原始抗体相比,展示了调制抗体的保留治疗疗效.
- 观察到调制抗体的改善药理动力学概况.
结论:
- 描述的可逆化学调制系统有效地减少了由Fc-FcγR结合引起的全身免疫激活.
- 这项技术提供了一个模块化方法,以减轻与Fc增强抗体相关的剂量限制毒性.
- 该方法有望在免疫瘤学中广泛应用,以改善基于抗体的药物的治疗指数.
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