Branched Linkers for Homogeneous Antibody-Drug Conjugates: How Long Is Long Enough? DOI Open Access
Evgeny L. Gulyak, О. В. Комарова,

Yuri Prokopenko

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13356 - 13356

Published: Dec. 12, 2024

Homogeneous antibody–drug conjugates (ADCs) exhibit significantly improved pharmacological properties compared to their heterogeneous counterparts. Site-specific conjugation of the payload IgG required for homogeneity can be achieved using enzymes. One example is microbial transglutaminase (MTGase), which selectively perform transamidation on Q295 residue human Fc when N297 glycans are removed. As a result, two modifications introduced per molecule; however, achieving higher drug-to-antibody ratios (DARs) requires use branched linkers. While several such linkers have been reported, little information available relationship between linker structure and ADC properties. To address this gap, we synthesized amino triazide linkers, differing by PEG4 fragment inserted after branching point, were used prepare homogeneous trastuzumab-based DAR 6 ADCs (a “short” “long” one). This was two-step process consisting enzymatic followed bioorthogonal coupling with cleavable bearing monomethyl auristatin E (MMAE). Two other trastuzumab–MMAE as controls: ADC, made conventional thiol–maleimide chemistry, 2 ADC. We found that, while four had identical affinity HER2, cytotoxicity differed significantly: just active its counterpart, but an order magnitude less potent, inferior even conjugate. Our findings indicate that length critically affects cytotoxic activity ADCs, possibly due steric hindrance influencing rate cleavage lysosomal

Language: Английский

Current Trends in Clinical Trials of Prodrugs DOI Creative Commons
Diogo Boreski,

Volkmar H.R. Schmid,

Priscila Longhin Bosquesi

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(2), P. 210 - 210

Published: Feb. 4, 2025

The development of new drugs is a lengthy and complex process regarding its conception ideation, passing through in silico studies, synthesis, vivo clinical trials, approval, commercialization, with an exceptionally low success rate. lack efficacy, safety, suboptimal pharmacokinetic parameters are commonly identified as significant challenges the discovery drugs. To help address these challenges, various approaches have been explored medicinal chemistry, including use prodrug strategies. As well-established approach, design remains best option for improving physicochemical properties, reducing toxicity, increasing selectivity, all while minimizing costs saving on biological studies. This review article aims to analyze current advances using approach that has allowed advance drug candidates trials last 10 years. presented here aim inspire further molecular optimization processes highlight potential this strategy facilitate advancement compounds study phases.

Language: Английский

Citations

0
Fluorogenic Platform for Real-Time Imaging of Subcellular Payload Release in Antibody–Drug Conjugates DOI Creative Commons
Ferran Nadal‐Bufí, Paulin Salomon,

Fabio De Moliner

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(9), P. 7578 - 7587

Published: Feb. 18, 2025

Antibody-drug conjugates (ADCs) represent promising therapeutic constructs to enhance the selective delivery of drugs target cells; however, attaining precise control over timing and location payload release remains challenging due complex intracellular processes that define ADC internalization, trafficking, linker cleavage. In this study, we present novel real-time fluorogenic probes monitor both subcellular dynamics trafficking release. We optimized a tandem molecular design sequential pH- enzyme-activatable naphthalimide fluorophores (1) track their localization along endolysosomal pathway (2) cleavage with OFF-to-ON fluorescence switches. Live-cell imaging microscopy revealed ADCs can traffic lysosomes yet require residence time in these compartments for efficient Notably, compact size naphthalimides did not impair recognition cell surface reporters or kinetics This modular platform is applicable many holds promise inform rational optimal profiles efficacy.

Language: Английский

Citations

0
Photocatalyzed elaboration of antibody-based bioconjugates DOI Creative Commons

Marine Le Stum,

Eugénie Romero,

Gary A. Molander

et al.

Beilstein Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: 21, P. 616 - 629

Published: March 18, 2025

Antibody–drug conjugates (ADCs) represent a promising class of targeted therapeutics, combining the specificity antibodies with potency cytotoxic drugs to enhance therapeutic efficacy while minimizing off-target effects. The development new chemical methods for bioconjugation is essential generate ADCs and optimize their stability, efficacy, safety. Traditional conjugation often face challenges related site-selectivity heterogeneous product mixtures, highlighting need develop new, innovative strategies. Photoredox chemistry emerges as powerful tool in this context, enabling precise, mild, selective modifications peptides proteins. By harnessing light drive transformations, photoredox techniques can facilitate synthesis antibody bioconjugates. This perspective will discuss empower applied functionalization.

Language: Английский

Citations

0
Late-Stage Desulfurization Enables Rapid and Efficient Solid-Phase Synthesis of Cathepsin-Cleavable Linkers for Antibody–Drug Conjugates DOI
Marzieh Ahangarpour, Margaret A. Brimble, Iman Kavianinia

et al.

Bioconjugate Chemistry, Journal Year: 2024, Volume and Issue: 35(7), P. 1007 - 1014

Published: June 14, 2024

The synthesis of linker-payloads is a critical step in developing antibody-drug conjugates (ADCs), rapidly advancing therapeutic approach oncology. conventional method for synthesizing cathepsin B-labile dipeptide linkers, which are commonly used ADC development, involves the solution-phase assembly B-sensitive dipeptides, followed by installation self-immolative para-aminobenzyl carbonate to facilitate attachment potent cytotoxic payloads. However, this often low yield and laborious, especially when extending peptide chain with components like glutamic acid improve mouse serum stability or charged amino acids poly(ethylene glycol) moieties enhance linker hydrophilicity. Here, we introduce novel utilizing late-stage desulfurization chemistry, enabling safe, facile, cost-effective access B-cleavable linker, Val-Ala-PABC-MMAE, on resin first time.

Language: Английский

Citations

1
Branched Linkers for Homogeneous Antibody-Drug Conjugates: How Long Is Long Enough? DOI Open Access
Evgeny L. Gulyak, О. В. Комарова,

Yuri Prokopenko

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13356 - 13356

Published: Dec. 12, 2024

Homogeneous antibody–drug conjugates (ADCs) exhibit significantly improved pharmacological properties compared to their heterogeneous counterparts. Site-specific conjugation of the payload IgG required for homogeneity can be achieved using enzymes. One example is microbial transglutaminase (MTGase), which selectively perform transamidation on Q295 residue human Fc when N297 glycans are removed. As a result, two modifications introduced per molecule; however, achieving higher drug-to-antibody ratios (DARs) requires use branched linkers. While several such linkers have been reported, little information available relationship between linker structure and ADC properties. To address this gap, we synthesized amino triazide linkers, differing by PEG4 fragment inserted after branching point, were used prepare homogeneous trastuzumab-based DAR 6 ADCs (a “short” “long” one). This was two-step process consisting enzymatic followed bioorthogonal coupling with cleavable bearing monomethyl auristatin E (MMAE). Two other trastuzumab–MMAE as controls: ADC, made conventional thiol–maleimide chemistry, 2 ADC. We found that, while four had identical affinity HER2, cytotoxicity differed significantly: just active its counterpart, but an order magnitude less potent, inferior even conjugate. Our findings indicate that length critically affects cytotoxic activity ADCs, possibly due steric hindrance influencing rate cleavage lysosomal

Language: Английский

Citations

0