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

Area of Science:

• Bioconjugation Chemistry
• Immunology
• Oncology

Background:

• Antibody-drug conjugates (ADCs) are crucial therapeutics due to their target specificity and potency.
• Existing ADC conjugation strategies often require complex antibody engineering.
• There is a need for advanced conjugation methods offering improved biocompatibility and controlled biophysical properties.

Purpose of the Study:

• To develop a novel site-specific conjugation strategy for ADCs using a bisecting glycan bridge.
• To demonstrate the efficacy of this strategy in creating anti-HER2 ADCs.
• To explore the potential for glycoengineering to modulate ADC properties.

Main Methods:

• A bisecting glycan-bridged conjugation approach was employed, bypassing the need for oligosaccharide synthesis or genetic antibody engineering.
• Human and mouse anti-HER2 IgGs were conjugated with monomethyl auristatin E using this strategy.
• The stability of the glycan bridge and the efficacy of the resulting ADCs against HER2-expressing cancer cells were evaluated.

Main Results:

• The glycan-bridged conjugation strategy enabled site-specific antibody modification.
• The developed ADCs demonstrated excellent stability and effectively eliminated HER2-expressing cancer cells.
• The strategy proved compatible with glycan structure remodeling for potential glycoengineering.

Conclusions:

• The bisecting glycan-bridged conjugation strategy offers a versatile and efficient method for creating site-specific ADCs.
• This approach facilitates the development of potent and stable ADCs with tunable pharmacokinetic and immunogenic profiles.
• The method holds promise for advancing ADC-based cancer therapies through simplified conjugation and glycoengineering.