有条件活跃的CD28xVISTA双特异抗体促进骨髓驱动的T细胞激活
Thomas Thisted1, F Donelson Smith1, Zhi-Gang Jiang1
1Sensei Biotherapeutics, Inc., Rockville, Maryland.
Cancer immunology research
|September 19, 2025
概括
我们开发了针对CD28和VISTA的pH选择性双特异性抗体 (bsAb),以增强T细胞介导的癌症杀伤,特别是在酸性瘤微环境中,减少全身副作用.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 生物技术是生物技术.
背景情况:
- 针对CD28的双特异性抗体 (bsAbs) 提供了一种有前途的策略,用于重振瘤反应性T细胞.
- 有条件的,针对瘤的T细胞的特定招募可以改善治疗控制和特异性.
- 酸性瘤微环境为向治疗提供了挑战和机会.
研究的目的:
- 开发pH选择性的CD28xVISTA bsAbs用于瘤微环境中的向T细胞激活.
- 为了增强T细胞介导的癌细胞杀死,同时最大限度地减少全身T细胞激活和细胞因子释放综合征.
- 在临床前模型中评估这些新型bsAbs的疗效和安全性.
主要方法:
- 设计了具有pH选择性的CD28xVISTA bsAbs与V域Ig组件.
- 在记者细胞系中评估了依赖pH的VISTA参与和CD28信号.
- 在试验室中评估T细胞激活,扩张和癌细胞杀死.
- 在一个人性化的CD28综基因小鼠模型中进行了体内疗效测试,该模型具有MC38瘤.
- 在体外测试中评估细胞因子释放综合征.
主要成果:
- 领先的CD28xVISTA bsAb候选体显示了pH依赖的VISTA参与和VISTA依赖的CD28信号传递.
- 试验室研究显示T细胞激活,扩张,并增强了癌细胞的杀死.
- 在人性化的小鼠模型中,bsAb有效地抑制了结合PD-1阻塞的瘤生长.
- 在实验室中没有观察到超级激素特性或显著的细胞因子释放综合征的迹象.
结论:
- 具有pH选择性的CD28xVISTA bsAbs可以有效地准瘤微环境,以增强癌症免疫疗法.
- 这些bsAbs促进T细胞激活和杀死癌细胞,具有良好的安全性.
- 这些发现支持CD28xVISTA bsAbs用于固体瘤的临床开发,可能与抗PD-1或抗CD3疗法结合使用.
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