最小化有效载荷溶剂暴露的疏水性表面积优化了抗体-药物结合物特性
Adrian D Hobson1, Haizhong Zhu2, Wei Qiu2
1AbbVie Bioresearch Center 381 Plantation Street Worcester Massachusetts 01605 USA adrian.hobson@abbvie.com.
RSC medicinal chemistry
|March 22, 2024
概括
对葡萄糖皮质体受体调节器 (GRM) 负载的晶体结构分析揭示了抗体-药物合物 (ADC) 设计的关键相互作用. 优化有效载荷特性,如降低疏水性,是有效的ADC开发在瘤学和免疫学的关键.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药用化学 医学化学
背景情况:
- 葡萄糖皮质体受体调节剂 (GRMs) 是重要的治疗药物,也是抗体-药物联合体 (ADC) 的有前途的有效载荷.
- 抗体与药物联合体 (ADCs) 通过杆向传递来提高瘤学和免疫学中的疗效.
- 优化ADC有效载荷属性对于治疗成功至关重要,并最大限度地减少非目标效应.
研究的目的:
- 为了阐明化合物2的晶体结构,在ABBV-3373和ABBV-154中使用了GRM有效载荷.
- 为了确定GRM有效载荷和葡萄糖皮质体受体 (GR) 连接体结合域之间的关键分子相互作用.
- 为改进的ADC有效载荷的合理设计提供见解.
主要方法:
- 采用X射线晶体学,确定与GR联体结合域结合的化合物2的结构.
- 结构分析的重点是结相互作用和立体化学.
- 对不同立体异构体 ((R) -和 (S) -乙) 的比较分析,以评估对有效载荷特性的影响.
主要成果:
- 晶体结构证实了GRM有效载荷 (化合物2) 和GR之间的四个关键键键,涉及氧功能组和特定的氨基酸残留物 (Gln570,Arg611,Asn564,Thr739).
- 在连接器附着部位确定了额外的键 (在二烯区域中的氨酸).
- 化合物2中的乙的 (R) 立体化学得到证实,与 (S) 乙 (化合物3) 的比较强调了尽量减少暴露的疏水表面积的重要性,以防止ADC聚合.
结论:
- 确定的晶体结构为GRM-GR相互作用提供了详细的分子理解.
- 尽量减少ADC有效载荷的疏水表面积对于改善它们的物理化学性质和体内行为至关重要.
- 这些发现有助于合理设计下一代GRM用于抗体药物合物的有效载荷,增强其治疗潜力.
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