Abstract
A novel enzyme cleavable linker for antibody-drug conjugates is reported. The 3-O-sulfo-β-galactose linker is cleaved sequentially by two lysosomal enzymes - arylsulfatase A and β-galactosidase - to release the payload in targeted cells. An α-HER2 antibody-drug conjugate synthesised using this highly hydrophilic dual-cleavable linker exhibited excellent cytotoxicity and selectivity.
MeSH terms
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Antineoplastic Agents, Immunological / chemistry
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Antineoplastic Agents, Immunological / metabolism
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Antineoplastic Agents, Immunological / pharmacology*
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Cell Survival / drug effects
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Cerebroside-Sulfatase / chemistry*
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Cerebroside-Sulfatase / metabolism
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Dose-Response Relationship, Drug
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Humans
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Hydrophobic and Hydrophilic Interactions
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Immunoconjugates / chemistry*
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Immunoconjugates / metabolism
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Molecular Structure
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Trastuzumab / chemistry
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Trastuzumab / metabolism
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Trastuzumab / pharmacology*
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beta-Galactosidase / chemistry*
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beta-Galactosidase / metabolism
Substances
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Antineoplastic Agents, Immunological
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Immunoconjugates
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Cerebroside-Sulfatase
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beta-Galactosidase
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Trastuzumab