In the evolving landscape of antibody–drug conjugate (ADC) development, the design of cleavable linkers is a decisive factor in achieving both therapeutic efficacy and selectivity.

Among the various enzymatically cleavable linker strategies, β-glucuronidase-cleavable linkers have established themselves as a robust and well-characterized option.

Why β-Glucuronidase-Cleavable Linkers?

These linkers remain stable in systemic circulation yet are selectively cleaved by β-glucuronidase—an enzyme commonly overexpressed in:

• The necrotic cores of tumors

• The broader tumor microenvironment in several solid malignancies

This ensures tumor-targeted payload release, while minimizing off-target toxicity and systemic side effects.

Structural Design and Variations

A typical β-glucuronidase-cleavable linker features a glucuronic acid unit conjugated at the anomeric position to a self-immolative spacer.

• The aminobenzyl alcohol motif is the classical choice for this role

• Several derivatives have since been developed to fine-tune performance, including:

  • Differently substituted aminobenzyl alcohols

  • Extended benzyl alcohol variants

  • Heteroaryl-linked spacers

These structural modifications allow chemists to optimize:

• Payload release kinetics

• Aqueous solubility

• Overall linker stability

Opportunities for ADC Development

This structural diversity provides researchers with the flexibility to tailor β-glucuronidase-cleavable linkers to specific therapeutic goals, while retaining the robust enzymatic trigger that ensures reliable release.

For ADC developers, the approach offers a balance of stability and tumor selectivity—key factors for advancing payload delivery strategies.

SigutLabs Expertise

At SigutLabs, we specialize in the custom synthesis of ADC linkers, including β-glucuronide linkers designed to meet the unique requirements of your ADC program.

Whether your goal is to maximize stability, modulate release kinetics, or explore new spacer architectures, our team is ready to support your innovation.

Contact us to discuss how we can help advance your next ADC project.