Discovery Biotherapeutics, Bristol-Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
Dren Bio, 400 Seaport Ct, Ste 102, Redwood City, California 94063, United States.
Bioconjug Chem. 2022 Apr 20;33(4):576-585. doi: 10.1021/acs.bioconjchem.1c00572. Epub 2022 Mar 28.
N-linked glycosylation is one of the most common and complex posttranslational modifications that govern the biological functions and physicochemical properties of therapeutic antibodies. We evaluated thermal and metabolic stabilities of antibody-drug conjugates (ADCs) with payloads attached to the C'E loop in the immunoglobulin G (IgG) Fc CH2 domain, comparing the glycosylated and aglycosylated Fc ADC variants. Our study revealed that introduction of small-molecule drugs into an aglycosylated antibody can compensate for thermal destabilization originating from structural distortions caused by elimination of N-linked glycans. Depending on the conjugation site, glycans had both positive and negative effects on plasma stability of ADCs. The findings highlight the importance of consideration for selection of conjugation site to achieve desirable physicochemical properties and plasma stability.
N-连接糖基化是最常见和最复杂的翻译后修饰之一，它控制着治疗性抗体的生物学功能和物理化学性质。我们评估了带有在 IgG Fc CH2 结构域中 C'E 环上连接的有效载荷的抗体药物偶联物 (ADC) 的热稳定性和代谢稳定性，比较了糖基化和非糖基化的 Fc ADC 变体。我们的研究表明，将小分子药物引入非糖基化抗体中可以补偿由于消除 N-连接聚糖引起的结构扭曲而导致的热不稳定性。根据缀合位点的不同，聚糖对 ADC 的血浆稳定性既有正面影响，也有负面影响。这些发现强调了在选择缀合位点以实现理想的物理化学性质和血浆稳定性时需要考虑的重要性。
