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Updated: Jan 7, 2026
11:02
Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
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Structural Characterization of Linker Shielding in ADC Site-Specific Conjugates
Maru Jaime-Garza1, Andrew Waight2, Manish Hudlikar1
1Discovery Chemistry, Merck & Co., Inc., 213 East Grand Ave., South San Francisco, CA 94080, USA.
Pharmaceutics
|December 31, 2025
Summary
Structural insights into antibody-drug conjugates (ADCs) reveal how antibody pockets can shield linker-payloads. This understanding can guide the design of more stable and effective ADCs through structure-based approaches.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Development
Background:
- Antibody-Drug Conjugates (ADCs) have advanced significantly but face challenges like aggregation and premature payload release.
- Site-specific conjugation improves ADC homogeneity, yet antibody-linker interactions at these sites are poorly understood.
Purpose of the Study:
- To elucidate the structural basis of antibody-linker interactions in site-specifically conjugated ADCs.
- To explore the potential of structure-based design for optimizing ADC linker chemistry.
Main Methods:
- Crystal structure determination of trastuzumab Fab and Fc domains site-specifically conjugated with a cleavable linker-payload.
Main Results:
- Identified potential pockets within both Fab and Fc regions of trastuzumab that interact with the linker-payload.
- These interactions suggest a shielding mechanism for the linker-payload by the antibody.
Conclusions:
- Structure-based design offers a promising avenue for optimizing ADC linker chemistry.
- Tailoring linker-payloads to specific antibody conjugation sites can enhance ADC stability and efficacy.
Keywords:
ADC structureFc engineeringX-ray crystallographyantibody–drug conjugates (ADCs)hydrophobicitylinker stabilitylinker–payload designsite-specific conjugationtrastuzumabMore Related Videos
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