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What makes an acid cleavable linker a stable linker?


Asked by Conrad Tucker on Dec 07, 2021 FAQ



Acid-cleavable linkers, such as hydrazone, are specifically designed to remain stable at the neutral pH of blood circulation, but undergo hydrolysis and release the cytotoxic drug in the acidic environment of the cellular compartments. These linkers have been associated with non-specific release of the drug in clinical studies.
Next,
Acid-labile linkers are a kind of chemically cleavable linkers which are the first to be used in early ADC constructs.
In addition, As one member of the cleavable linkers, pH-sensitive linkers (also refered to as acid-labile linekrs), such as hydrazones, are based on the a nonspecific pH sensing mechanism to achieve payload release. pH-sensitive linkers (acid-labile linkers), are a class of chemically cleavable linkers that were first used in early ADC developments.
Consequently,
Non-cleavable linker has no obvious drug release mechanism, and the ADC prepared by this strategy relies on the complete lysosomal proteolytic degradation of the antibody that releases the antibody-drug after internalization.
In this manner,
By design, they retain intact and stable during systemic circulation in the blood’s neutral pH environment (pH 7.3-7.5). Once internalized, upon sensing of the mildly acidic pH of the endosomal (pH 5.0-6.5) or lysosomal (pH 4.5-5.0) compartments of the cell, the pH-sensitive linkers undergo rapid hydrolysis and thus release the payload drug.