Non-cleavable Linkers

Non-cleavable Linkers

Non-cleavable linkers require mAb degradation within lysosomes after ADC internalization to release the active drug. BOC Sciences provides synthetic non-cleavable linker products with a wide range of scales, purities, and delivery time options to meet your research needs. We ensure that each custom linker product is multiple-checked for quality via both mass spectrometry (MS) and high-performance liquid chromatography (HPLC) analyses during linker purification and quality control (QC) procedures after each step.


Non-cleavable linkers require the complete degradation of antibodies in lysosomes to release payloads, and their cleavages are more stable in plasma than cleavable linkers. Furthermore, cytotoxins are not released outside the target cell, reducing its toxicity toward healthy cells. Despite limited bystander effects, cleavage resistance outside of target cells may increase the specificity of drug release. Several in vivo studies and clinical data, for example, have demonstrated that non-cleavable linked ADCs outperform their cleavable counterparts in vivo. Numerous non-cleavable linkers have been explored in ADC development, the most representative being SMCC. These linkers are used in hematological tumors and cancers with high antigen expression.

Non-cleavable Linkers Pharmaceuticals (Basel). 2021, 14(5): 422.

Compared to cleavable linkers, the greatest advantage of non-cleavable linkers involved increased plasma stability. Non-cleavable linked ADCs have outperformed the cleavable counterparts in vivo, and mAb degradation within the lysosome after ADC internalization is required for active drug releases from non-cleavable linkers. Potentially, non-cleavable linkers can provide a greater therapeutic window than cleavable linkers because payload derivatives from non-cleavable ADCs can eliminate target cells effectively. In addition, a potentially reduced off-target toxicity is expected compared to the cleavable linker conjugates because non-cleavable ADCs support greater stability and tolerability.

Designing Process Requirements

Non-cleavable Linkers 2

Mechanistically, non-cleavable linkers are resistant to proteolytic degradation and usually rely on full degradation of the antibody to release attached linker-payload complexes. This mechanism requires the payload to remain active while linker bound. For example, MMAE is a protein-based anti-mitotic drug and most potent in its native form; therefore, it is poorly suited for derivitization with a non-cleavable linker. On the other hand, MMAF retained its potency even when linked with a simple alkyl chain in vitro and in vivo. Due to this, non-cleavable linkers were proposed as a strategy to overcome drug resistance since the linker-payload complex is no longer the substrate for multiple drug resistance. Therefore, the proposed action mechanism of the ADC can be a determinant for linker choice.

Our Services

  • Design of Thioether Linker
Non-cleavable Linkers 3

Several non-cleavable alkyl and polymeric linkers have been explored in ADC development. A notable example is MCC, which couples the payload with the antibody via a thioether bond. Furthermore, this linker is especially useful as the cyclohexane ring provides a steric hindrance that decreases the hydrolysis of the resulting thioether. With years of ADC research, development and production capabilities, BOC Sciences' scientists can select and design the most appropriate payload structure combined with a non-cleavable linker and play to its most superior anti-tumor efficacy.

  • Design of Amide Linker
Non-cleavable Linkers 4

Amide linker is a non-cleavable stable linker. After being phagocytized by tumor cells, the ADC antibody is degraded in the lysosome, releasing small molecule cytotoxin with amide linker and exerting anti-tumor effects. Stable amide bonds are increasingly used to improve the stability and tolerability of ADC drugs in the blood circulation and intracellular environment. BOC Sciences provides a one-stop platform for small molecule ADC development and manufacturing from preclinical to commercial stages. In BOC Sciences, we strive to offer a comprehensive range of services, including synthetic development, process development, ADC analysis and characterization, and commercial supply production.

What Can We Do For You?

BOC Sciences has developed highly integrated approaches that can uniquely customize the best combination of linkers and conjugation chemistry. For years, we have provided a full range of payloads, custom synthesis, and antibody conjugation services to our clients worldwide. Our highly skilled Ph.D. and M.S. synthetic chemists are prepared to solve the questions you may have encountered during your ADC drug research.

Our Linker Development Workflow

Linker Development Workflow


  1. Owen, S.C. Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. The AAPS Journal, 2015, 17(2): 339-351.
  2. Kotschy, A. et al. The chemistry behind ADCs. Pharmaceuticals (Basel). 2021, 14(5): 422.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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