Exolinkers: A New Strategy to Overcome Val-Cit Linker Drawbacks

The valine-citrulline (Val-Cit) linker is a cleavable peptide linker that can be cleaved by cathepsin B, a protease highly expressed in cancer cells, which confers specificity of the Antibody-drug conjugates (ADCs) to cancer cells. Although the Val-Cit linker is widely used in many FDA-approved ADCs, it is still associated with several limitations, including:

A recent study proposed a novel linker to address the intrinsic limitations of the Val-Cit linker (Fig 1). Breaking away from the conventional linear "Antibody-Linker-Payload" structure, the researchers developed an innovative design that repositions the cleavable peptide linker at the exo position of the p-aminobenzylcarbamate moiety (Fig 1). In this design, exolinkers offer a new strategy for improving therapeutic efficacy and safety profiles of ADCs.

Fig 1. Comparison of Val-Cit PAB (A) and exo-cleavable linkers (B)

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