Site-Specific Antibody Conjugation Using Modified Bisected <i>N</i>-Glycans: Method Development and Potential toward Tunable Effector Function
Yen‐Pang Hsu, Omar Nourzaie, Ariel E. Tocher, Kavitha Nerella, Grigori Ermakov, Ji‐Won Jung, Alexandra Fowler, Peidong Wu, Umme Ayesa, Aarron Willingham, Maribel Beaumont, Sampat Ingale
Abstract
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.