Biotech Informers

Antibody drug conjugates (ADCs) are a class of targeted cancer therapies that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxic potency of small molecule drugs. These complex molecules consist of three components: the mAb, the cytotoxic drug, and the linker that connects them. The linker plays a critical role in ADCs as it determines the stability, pharmacokinetics, and efficacy of the final product. In this article, we will focus on the difference between cleavable and non-cleavable linkers used in ADCs.

Cleavable Linkers

Cleavable linkers are designed to release the cytotoxic drug in response to certain conditions, such as the acidic environment of tumors or the presence of specific enzymes. This mechanism of action allows for targeted drug delivery to cancer cells and reduces off-target toxicity. There are several types of cleavable linkers used in ADCs, including acid-labile, enzymatically-cleavable, and reducible linkers.

Acid-labile linkers are pH-sensitive and break down in the acidic environment of the tumor. These linkers typically contain a hydrazone or a maleimide bond that is cleaved at low pH, releasing the drug payload. One example of an acid-labile linker is the hydrazone linker used in the ADC Adcetris (brentuximab vedotin), which is approved for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma.

Enzymatically-cleavable linkers are designed to release the drug payload in response to specific enzymes that are overexpressed in cancer cells. Examples of enzymatically-cleavable linkers include peptide linkers that are cleaved by proteases or glycosidic linkers that are cleaved by glycosidases.

Reducible linkers contain a disulfide bond that is cleaved by the high levels of reducing agents, such as glutathione, found in the cytosol of cancer cells. These linkers are used in ADCs that target intracellular proteins, such as tubulin.

Non-cleavable Linkers

Non-cleavable linkers, as the name suggests, do not release the drug payload from the mAb. Instead, the entire ADC is internalized into the cancer cell, where the drug is released by lysosomal degradation of the mAb. Non-cleavable linkers have the advantage of greater stability and longer half-life, as they are not subject to linker cleavage or drug release. However, they also have the disadvantage of potentially higher off-target toxicity, as the drug payload is not specifically targeted to cancer cells.

One example of a non-cleavable linker is the thioether linker used in the ADC Kadcyla (ado-trastuzumab emtansine), which is approved for the treatment of HER2-positive breast cancer. Kadcyla consists of the mAb trastuzumab conjugated to the cytotoxic drug DM1 via a thioether linker. The entire ADC is internalized into the cancer cell, where the DM1 is released by lysosomal degradation of the mAb.

Conclusion

Cleavable and non-cleavable linkers are two types of linkers used in ADCs, each with its advantages and disadvantages. Cleavable linkers allow for targeted drug delivery to cancer cells and reduced off-target toxicity, while non-cleavable linkers provide greater stability and longer half-life. The choice of linker depends on the specific characteristics of the ADC, including the target antigen, the cytotoxic drug, and the desired mechanism of action.