Non-cleavable Linker

With state-of-art equipment, advanced techniques, and well-established “DrugLnk” organic synthesis platform, scientists from Creative Biolabs have explored several different non-cleavable linkers for the development of antibody-drug conjugates (ADCs).

Linkers dictate the drug release mechanism of an ADC (cleavable vs. non-cleavable) and they also contribute significantly to various ADC biochemical features. Non-cleavable linkers are a novel class of new generation linkers with improved plasma stability compared to many cleavable linkers. Non-cleavable linkers have no obvious drug release mechanism and ADCs prepared by this strategy relies on the complete lysosomal proteolytic degradation of the antibody after internalization to release the payload drug. Through this degradation, the non-cleavable linker carrying the drug will also be coupled with the conjugation amino acid from the antibody. Thus, ADCs with non-cleavable linkers are more dependent on the biology of the target cell compared to cleavable linkers.

Moreover, ADCs developed with non-cleavable linkers have improved therapeutic index due to their greater plasma stability. Despite the limited “bystander” effect, the resistance to extracellular cleavage may actually increase the specificity of drug release. For example, many in vivo studies and clinical data have shown that ADCs bearing non-cleavable linkers outperform the efficacy of their cleavable counterparts.

An example of an ADC prepared via  the conjugation of auristatin MMAF to the antibody via a non-cleavable  maleimidoca-proyl (MC) linker (Methods.  Mol. Biol., 2013). An example of an ADC prepared via the conjugation of auristatin MMAF to the antibody via a non-cleavable maleimidoca-proyl (MC) linker (Methods. Mol. Biol., 2013).

Creative Biolabs can provide several noncleavable alkyl and polymeric linkers, such as the notablely successful MCC amine-to-sulfhydryl bifunctional cross-linker featured in T-DM1. This linker is especially useful as the cyclohexane ring provides steric hindrance that decreases the rate of hydrolysis of the resulting thioether. Non-cleavable thioether linkers, succinimide-thioether bonds that formed by the reaction of maleimids with thiols, have also been commonly used to link auristatin derivatives to monoclonal antibodies.

MMAE, a protein-based anti-mitotic drug, is most potent in its native form and is therefore poorly suited for derivitization with non-cleavable linkers. On the contrary, MMAF, another auristatin derivative, has been shown to retain its in vitro and in vivo potency even when coupled with an alkyl chain. Unfortunately, in some cases, a decreased payload potency is observed when using non-cleavable linkers. One proposed mechanism for the potency decrease is that drugs coupled with charged amino acids often exert compromised membrane permeability, limiting their “bystander” effect to kill nearby cells. Therefore, to improve such “bystander” effect, cleavable linkers are sometimes used. Generally, there is no fixed guideline for linker selection. This is an intricate balance between stability and efficacy. Even though the goal is to achieve both, sometimes compromises have to be made.

To fulfill customers’ specific demands, Creative Biolabs provides unmatched customized-design services for non-cleavable linkers depending on the antibody, drug and, tumor target. We will design and select the most suited linker evaluated based on efficacy and toxicity of an individual ADC construct. In the meantime, we also provide other services for the benefit of ADC development. Please feel free to contact us for more information and a detailed quote.


  1. Nolting, B.; et al. Linker technologies for antibody-drug conjugates. Methods. Mol. Biol. 2013, 1045: 71-100.
  2. Jain, N.; et al. Current ADC linker chemistry. Pharm. Res. 2015, 32: 3526-3540.
  3. McCombs, J.R.; Owen, S.C. Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. AAPS J. 2015, 17(2): 339-351.

For lab research use only, not for any in vivo human use.

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