MRL, Merck & Co., Inc., 320 Bent St., Cambridge, Massachusetts 02141, United States.
MRL, Merck & Co., Inc., 213 E. Grand Ave., South San Francisco, California 94080, United States.
Bioconjug Chem. 2023 Sep 20;34(9):1633-1644. doi: 10.1021/acs.bioconjchem.3c00302. Epub 2023 Aug 24.
Antibody-drug conjugates (ADCs) have garnered worldwide attention for disease treatment, as they possess high target specificity, a long half-life, and outstanding potency to kill or modulate the functions of targets. FDA approval of multiple ADCs for cancer therapy has generated a strong desire for novel conjugation strategies with high biocompatibility and controllable bioproperties. Herein, we present a bisecting glycan-bridged conjugation strategy that enables site-specific conjugation without the need for the oligosaccharide synthesis and genetic engineering of antibodies. Application of this method is demonstrated by conjugation of anti-HER2 human and mouse IgGs with a cytotoxic drug, monomethyl auristatin E. The glycan bridge showed outstanding stability, and the resulting ADCs eliminated HER2-expressing cancer cells effectively. Moreover, our strategy preserves the feasibility of glycan structure remodeling to fine-tune the immunogenicity and pharmacokinetic properties of ADCs through glycoengineering.
抗体药物偶联物（ADCs）在疾病治疗方面引起了全球关注，因为它们具有高靶向特异性、长半衰期和出色的杀伤或调节靶标功能的能力。FDA 批准了多种用于癌症治疗的 ADC，这激发了人们对具有高生物相容性和可控生物特性的新型偶联策略的强烈需求。在这里，我们提出了一种双分叉糖基桥接偶联策略，该策略能够实现定点偶联，而无需合成寡糖和对抗体进行基因工程改造。通过将抗 HER2 人源和鼠源 IgG 与细胞毒性药物单甲基澳瑞他汀 E 偶联，证明了该方法的应用。糖基桥表现出优异的稳定性，所得 ADC 有效地消除了表达 HER2 的癌细胞。此外，我们的策略通过糖基工程保留了糖基结构重塑的可行性，以微调 ADC 的免疫原性和药代动力学特性。
