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Cleavable vs. Non Cleavable Linkers in Antibody Drug Conjugates .pdf

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Cleavable vs. Non-Cleavable Linkers in AntibodyDrug Conjugates
Antibody-drug conjugates (ADCs) are now established as the main therapies
for clinical cancer treatment. The principle of ADCs is based on monoclonal
antibodies, which specifically direct toxic agents to diseased tissues while
minimizing peripheral damage to healthy tissues.

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.

One of the main challenges in developing safe and effective antibody-drug
conjugates is the generation of suitable chemical linkers between cytotoxic
drugs and monoclonal antibodies. A stable ADC linker ensures that less
cytotoxic payloads fall off before reaching tumor cells, increasing safety and
limiting dose.

In antibody-drug conjugates currently approved by the US FDA, two common
ways of linking cytotoxic anticancer agent payloads include cleavable and
non-cleavable linkers.



Cleavable linkers play a key role in the success of antibody-drug conjugates.
They use the inherent properties of tumor cells to selectively release
cytotoxins from ADCs. They are stable in the blood circulation for a long
period of time. There are three commonly used mechanisms: 1) protease
sensitivity, 2) pH sensitivity, and 3) glutathione sensitivity.

The protease sensitivity strategy utilizes predominant proteases found in
lysosomes of tumor cells to recognize and cleave specific peptide sequences
in the linker. Dubowchik and Firestone et al. pioneered the discovery of the
valine-citrulline (VC) dipeptide as an intracellular cleavage mechanism by
cathepsin B.

The acid-sensitive strategy is to use a lower pH of the endosome (pH = 5-6)
and lysosome (pH = 4.8) compartments compared to the cytoplasm (pH = 7.4)
to trigger the hydrolysis of an acid-labile group within the linker, such as a

The third release strategy utilizes higher intracellular glutathione
concentrations than in plasma. Therefore, the disulfide-containing linker
releases cytotoxins after reduction by glutathione.

Non-cleavable linker has no obvious drug release mechanism, and the ADC
prepared by this strategy relies on the complete lysosomal proteolytic
degradation of the antibody that releases the antibody-drug after
internalization. Through this degradation, the non-cleavable linker carrying the
drug will also be coupled to the conjugated amino acid of the antibody.
Therefore, ADCs with non-cleavable linkers are more dependent on the
biology of the target cells than cleavable linkers.

One of the advantages of non-cleavable linkers over cleavable linkers is their
increased plasma stability, which can improve the therapeutic index. Studies



have shown that non-cleavable linked ADCs generally perform better than
their cleavable counterparts in vivo.

Moreover, due to the fact that payload derivatives from non-cleavable ADCs
can kill target cells, non-cleavable linkers can potentially provide a larger
therapeutic window compared to cleavable linkers. Finally, it is expected to
reduce off-target toxicity compared to cleavable linker conjugates because
non-cleavable ADCs can provide greater stability and tolerance.

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