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Stable Linker (technologies)

Recent advances in the development of antibody-drug conjugates are primarily based on the development of stable linkers.  Previously antibody-drug conjugates were made with linkers that released the cytotoxin anticancer agent prematurely, before arriving at the target cell.  

A new generation of linkers is more stable in circulation, but retains the ability to be labile after cellular binding.

Two predominant technologies
There are two common ways to link cytotoxic anticancer agents  or “payloads” to antibodies in ADCs: non-cleavable and cleavable linkers.  For example, brentuximab vedotin (ADCETRIS®; Seattle Genetics) features the cleavable linker vcMMAE, while ado-trastuzumab emtansine (Kadcyla; Genentech/Roche) contains the non-cleavable linker SMCC. In either case, the stability of the antibody-drug conjugate during delivery to the target site is key to achieving a desirable therapeutic index.

Cleavable linkers
Cleavable linkers take advantage of the antibody-drug conjugate targeting mechanism which involves sequential binding of the antibody-drug conjugate to its cognate antigen on the surface of the target cancer cells, and internalization of the ADC-antigen complexes through the endosomal–lysosomal pathway. Intracellular liberation of the cytotoxin in these cases relies on the fact that endosomes/lysosomes are acidic compartments that will facilitate cleavage of acid-labile chemical linkages such as hydrazone. In addition, if a lysosomal-specific protease cleavage site is engineered into the linker, for example the cathepsin B site in vcMMAE, the cytotoxins will be liberated in proximity to their intracellular targets. Alternatively, linkers containing mixed disulfides provide yet another approach by which cytotoxic payloads can be liberated intracellularly as they are selectively cleaved in the reducing environment of the cell, but not in the oxygen-rich environment in the bloodstream.

Non-cleavable linkers
Non-cleavable linkers liberate toxic payloads during lysosomal degradation of the antibody-drug conjugate within the target cell.

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