Disulfide re-bridging reagents for single-payload antibody-drug conjugates

King, Thomas A.; Walsh, Stephen J.; Kapun, Mia; Wharton, Thomas Kelah; Krajčovičová, Soňa; Glossop, Melanie S.; Spring, David R.

doi:10.1039/d3cc02980h

“…The authors have cited additional references within the Supporting Information. [59][60][61][62] F.C-W. and R.A.F. thank the Cystic Fibrosis Trust UK [Innovation Hub grant 001, the Wellcome Trust (107032AIA, 226602/Z/22/Z),] and W.D Armstrong Studentship Trust.…”

Section: Supporting Informationmentioning

confidence: 99%

Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

Wharton,

Crawshay‐Williams,

Schober

et al. 2024

Angew Chem Int Ed

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The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload‐release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials. Herein, is presented a comprehensive strategy for the controlled and selective release of a diverse range of amides with stable linkers. The versatility of this approach is demonstrated by its successful application in the targeted release of various amide‐containing drugs in their natural form via the use of commonly used trigger motifs, such as dipeptides or glycosides. As a proof‐of‐concept, the FDA‐approved antibiotic linezolid has been successfully converted into a prodrug form and released selectively only in the presence of the trigger event. Significantly, in its prodrug state, no activity against Mycobacterium tuberculosis was exhibited. Linezolid's full potential was achieved only upon controlled release, where an equipotent efficacy to the free linezolid control was demonstrated, thus emphasising the immense potential of this method.

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“…Alkynes have also been employed for rebridging via thiol–yne coupling or via their incorporation in diethynyl phosphinates . Other examples of rebridging reagents include organic arsenicals, divinylpyrimidines, − arylene dipropiolonitriles (ADPN), di(bromomethyl)pyridines, diPODS, or oxSTEF reagents …”

Section: Introductionmentioning

confidence: 99%

Fluorine-18 and Radiometal Labeling of Biomolecules via Disulfide Rebridging

Richard,

Martin Aubert,

Denis

et al. 2023

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Biomolecules labeled with positron-emitting radionuclides like fluorine-18 or radiometals like copper-64 and zirconium-89 are increasingly employed in nuclear medicine for diagnosis purposes. Given the fragility and complexity of these compounds, their labeling requires mild conditions. Besides, it is essential to develop methods inducing minimal modification of the tertiary structure, as it is fundamental for the biological activity of such complex entities. Given these requirements, disulfide rebridging represents a promising possibility since it allows protein modification as well as conservation of the tertiary structure. In this context, we have developed an original radiofluorinated dibromopyridazine dione prosthetic group for labeling of disulfide-containing biomolecules via rebridging. We employed it to radiolabel octreotide, a somatostatin analogue, and to radiolabel fragment antigen binding (Fab) targeting programmed death-ligand 1 (PD-L1), whose properties were then evaluated in vitro and in vivo by positron emission tomography (PET) imaging. We next extended our strategy to the radiolabeling of cetuximab, a monoclonal antibody, with various radiometals commonly used in PET imaging (zirconium-89, copper-64) by developing various rebridging molecules bearing the appropriate chelators. The stabilities of the radiolabeled antibody conjugates were assessed in biological conditions.

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Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

Wharton,

Crawshay‐Williams,

Schober

et al. 2024

Angewandte Chemie

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1

0

View full text Add to dashboard Cite

The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload‐release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials. Herein, is presented a comprehensive strategy for the controlled and selective release of a diverse range of amides with stable linkers. The versatility of this approach is demonstrated by its successful application in the targeted release of various amide‐containing drugs in their natural form via the use of commonly used trigger motifs, such as dipeptides or glycosides. As a proof‐of‐concept, the FDA‐approved antibiotic linezolid has been successfully converted into a prodrug form and released selectively only in the presence of the trigger event. Significantly, in its prodrug state, no activity against Mycobacterium tuberculosis was exhibited. Linezolid's full potential was achieved only upon controlled release, where an equipotent efficacy to the free linezolid control was demonstrated, thus emphasising the immense potential of this method.

show abstract

Disulfide re-bridging reagents for single-payload antibody-drug conjugates

Abstract: Numerous antibody-drug conjugate (ADC) linker technologies exist for the synthesis of ADCs with drug-to-antibody ratios (DARs) being an even integer (typically 2, 4 or 8). However, ADCs with odd-integer DARs...

Cited by 5 publications

References 12 publications

Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

Fluorine-18 and Radiometal Labeling of Biomolecules via Disulfide Rebridging

Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

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