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Stable Linker (Technologies)

ADC Review

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

Over the pas half decade linker strategies took on greater importance in the development of antibody-drug conjugates. The synthesis is quite complex and several aspects must be critically balanced to guarantee efficacy.

One of the unique features of ADCs is that they offer a unique-targeted therapeutic strategy by combining the best features of both antibodies and small-molecule drugs to create a single moiety that is highly specific and cytotoxic.

High drug-linker stability in circulation
However, one of the biggest challenges in the development of antibody-drug conjugates is the generation of suitable linkers offering high drug-linker stability in circulation for the conjugation of antibody and drug. Chemically labile linkers, such as hydrazones and disulfides, may offer limited plasma stability. Peptide-based linker technologies may offer better controled drug-linker stability d and drug release. Peptidic bonds are expected to have good serum stability. Cleavable dipeptide linkers like Val-Ala and Val-Cit rely on processes inside the cell to liberate the payload, as they undergo rapid hydrolysis in the presence of lysosomal extracts or purified human cathepsin B.

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.

Failing to realize potential
As a result of the complexity of linker chemistry, a number of antibody-drug conjugates that initially showed promising preclinical data have failed to realize their potential. However, the latest generation of antibody-drug conugates is now showing great promise in early clinical trials.

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