Site-Specific Antibody Conjugation Using Modified Bisected N-Glycans: Method Development and Potential toward Tunable Effector Function

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.

Automated summary

Antibody-drug conjugates (ADCs) are attracting global attention for disease treatment due to their target specificity, long half-life, and potent ability to modulate targets. This article presents a bisecting glycan-bridged conjugation strategy that enables site-specific conjugation without the need for oligosaccharide synthesis and genetic engineering. The application of this strategy is demonstrated by conjugating anti-HER2 human and mouse IgGs with a cytotoxic drug, monomethyl auristatin E, resulting in stable ADCs that effectively eliminate HER2-expressing cancer cells. Furthermore, this strategy allows for glycan structure remodeling to fine-tune the immunogenicity and pharmacokinetic properties of ADCs through glycoengineering.