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Stable Linker (Technologies)


Linker Technologies

  • Type of chemical linkers
  • Stability in circulation
  • Prominent technologies

Antibody–drug conjugates (ADCs) or immunoconjugates have shown to offer the unique benefits of a targeted therapeutic strategy combined with the best features of both therapeutic monoclonal antibodies (mAb) and potent small-molecule cytotoxic drugs through a linker that is stable within systemic circulation but cleaves within the target cells, to create a single moiety that is highly specific to numerous cancer cells. Simply states, the principle behind of antibody-drug conjugates is based on the monoclonal antibody guiding the toxic agent specifically to diseased tissue, while minimizing the peripheral damage to healthy tissue.[5]

The development of ADC involves a critical understanding of target antigen selection, conjugate internalization by tumor cells, drug potency and stability of the linker between drug and antibody. Furthermore, understanding the conjugation methods, drug-to-antibody ratio or DAR, the effects of drug conjugation on antibody properties and kind of linker are critical in developing safe and effective ADCs using highly potent anticancer agents. [1]

One of the major challenge in the in the development of safe and effective antibody-drug conjugates has been the generation of suitable chemical linkers between the cytotoxic drug and the monoclonal antibody. While the synthesis of linker chemistry is quite complex and several aspects must be critically balanced to guarantee efficacy, ultimately, the nature of the chemical linker being used shapes the release profile of the cytotoxin.

Important considerations
Among the important considerations is the fact that monoclonal antibodies have circulation half lives of multiple days, hence, a linker with stability at systemically relevant pHs for multiple days is preferable. Also, conjugation of the linker and toxin should not adversely affect the stability of the monoclonal antibody.

Failing to realize their 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 real potential. These 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.  Based on these lackluster results, linker strategies have, over the pas half decade, taken on greater importance in the development of antibody-drug conjugates. The latest generation of antibody-drug conjugates with improved linker chemistries are now showing great promise in early clinical trials

Limited number of linkers
The majority of antibody-drug conjugates currently in clinical development use only a limited number of chemical linkers, including hydrazones, disulfides, peptides or thioether bonds.  Principally, theses chemical linkers exploit the differences in intracellular pH, reduction potential or enzyme concentration to trigger the release of the cytotoxin in the cell.

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 and drug release. Peptidic bonds are also 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.

Two predominant technologies
In the currently U.S. FDA approved antibody-drug conjugates two common ways to link cytotoxic anticancer agents payloads include non-cleavable (a non-cleavable thioether linker that releases the drug after the monoclonal antibody is degraded) and cleavable linkers (a peptide linker cleaved by cathepsin B).

For example, brentuximab vedotin (Adcetris®; Seattle Genetics) or cAC10-valine-citrulline-MMAE, features a  protease-sensitive dipeptide linker designed to release MMAE by lysosomal cathepsin B in target cells but maintain a stable linkage and attenuate drug potency in circulation, 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.[2]

Cleavable linkers
Cleavable dipeptide linkers like Val-Ala and Val-Cit 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.

In these cases, intracellular release of the cytotoxic anticancer drug 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 are an important component of antibody-drug conjugates. The liberate the cytotoxic small molecule payload during  lysosomal degradation of the antibody-drug conjugate within the target cell, thus avoiding non-specific release of the drug.  Furthermore, non-cleavable linkers allow the chemical properties of the small molecule to be altered to tune affinity for the transporter or improve potency.

Last editorial review: March 31, 2015

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