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Related Experiment Video

Updated: Jan 7, 2026

Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction

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

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.

|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.

Keywords:

ADC structure Fc engineering X-ray crystallography antibody–drug conjugates (ADCs)hydrophobicity linker stability linker–payload design site-specific conjugation trastuzumab

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Efficient and Site-specific Antibody Labeling by Strain-promoted Azide-alkyne Cycloaddition

Efficient and Site-specific Antibody Labeling by Strain-promoted Azide-alkyne Cycloaddition

Published on: December 23, 2016

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Last Updated: Jan 7, 2026

Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction

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

Synthesis and Bioconjugation of Thiol-Reactive Reagents for the Creation of Site-Selectively Modified Immunoconjugates

Synthesis and Bioconjugation of Thiol-Reactive Reagents for the Creation of Site-Selectively Modified Immunoconjugates

Published on: March 6, 2019

Efficient and Site-specific Antibody Labeling by Strain-promoted Azide-alkyne Cycloaddition

Efficient and Site-specific Antibody Labeling by Strain-promoted Azide-alkyne Cycloaddition

Published on: December 23, 2016

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.