Bifunctional Linker for ADC Synthesis with β-Glucuronidase-Triggered Drug Release

MAC glucuronide linker-2 is a bifunctional linker designed to enable β-glucuronidase-responsive drug release for the synthesis of antibody–drug conjugates (ADCs). Reports indicate that ADCs incorporating a glucuronide moiety in the linker releases its payload after cellular internalization, through a glycosidic hydrolysis reaction catalyzed by β-glucuronidase present in lysosomes.¹⁾ While sharing the same design concept as the widely used enzymatically cleavable valine-citrulline motif, the hydrophilicity derived from glucuronic acid has been suggested to improve physicochemical properties during the design and preparation of ADCs, particularly where hydrophobicity-driven aggregation is a concern.^2-5)

Related Products

M3763

MAC Glucuronide Linker-2

F1405

4-Formyl-2-nitrophenyl 2,3,4,6-Tetra-O-acetyl-β-D-galactopyranoside

Related Products Category Page

• Enzyme Cleavable Linkers (Cleave Motif) [Regents for ADC Preparation Research]

References

• 1) Development and Properties of β-Glucuronide Linkers for Monoclonal Antibody−Drug Conjugates
  • S. C. Jeffrey, J. B. Andreyka, S. X. Bernhardt, K. M. Kissler, T. Kline, J. S. Lenox, R. F. Moser, M. T. Nguyen, N. M. Okeley, I. J. Stone, X. Zhang, P. D. Senter, Bioconjugate Chem. 2006, 17, 831.
• 2) Design, Synthesis, and Biological Evaluation of Antibody−Drug Conjugates Comprised of Potent Camptothecin Analogues
  • P. J. Burke, P. D. Senter, D. W. Meyer, J. B. Miyamoto, M. Anderson, B. E. Toki, G. Manikumar, M. C. Wani, D. J. Kroll, S. C. Jeffrey, Bioconjugate Chem. 2009, 20, 1242.
• 3) Optimization of a PEGylated Glucuronide-Monomethylauristatin E Linker for Antibody–Drug Conjugates
  • P. J. Burke, J. Z. Hamilton, S. C. Jeffrey, J. H. Hunter, S. O. Doronina, N. M. Okeley, J. B. Miyamoto, M. E. Anderson, I. J. Stone, M. L. Ulrich, J. K. Simmons, E. E. McKinney, P. D. Senter, R. P. Lyon, Mol. Cancer Ther. 2017, 16, 116.
• 4) Anti-HER2, High-DAR Antibody Fragment–Drug Conjugates with a Glucuronide-Based MMAE Linker–Payload Demonstrate Superior Efficacy over IgG-Based ADCs
  • I. Stamati, G. Yahioglu, S. Diez-Posada, A. Pomowski, I. Perez-Castro, A. Stewart, L. Bouché, A. Constantinou, B. J. Stenton, S. Saouros, B. Edwards, S. Ness, M. P. Deonarain, Mol. Cancer Ther. 2025, 24, 1295.
• 5) Site-Selective Anti-PD-L1 Antibody–MMAE Conjugate for Enhanced NSCLC Therapy
  • S. J. Kwon, J. Son, S. J. Chung, ACS Med. Chem. Lett. 2025, 16, 1131.

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