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:
• Hydrophobicity-induced aggregation
• Limited drug−antibody ratio (DAR)
• Premature payload release
To address the hydrophobicity of the Val-Cit platform, various strategies have been developed, such as incorporating hydrophilic polymer scaffolds like PEG[1], polysarcosine[2], cyclodextrins[3], peptides[4], and polyacetals[5]. Notably, a recent study[6] 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 1B).
Fig 1. Comparison of Val-Cit PAB (A) and exo-cleavable linkers (B)
In this design, the linker is positioned externally, bringing the payload closer to the antibody. This arrangement enhances shielding by the antibody, significantly improving hydrophilicity. Additionally, the hydrophilic Glu-containing linker not only resists carboxylesterase Ces1C but also prevents premature payload detachment mediated by human neutrophil elastase (NE), contributing to an improved safety profile. In vitro and in vivo evaluations showed that exolinker ADCs reduced premature payload release, increased drug-to-antibody ratios, and avoided significant aggregation, even with hydrophobic payloads. Overall, exolinkers offer a new strategy for improving therapeutic efficacy and safety profiles of ADCs.
ChemExpress leads the field for ADC drug development providing one-stop CRO & CDMO services for both linkers, payloads and ADC conjugation. We have a substantial inventory of 80+ payloads and 400+ linkers, in addition to 1000+ successful linker compound syntheses. These include hydrophilic polymer scaffolds like PEG, polysarcosine, cyclodextrins, peptides, and polyacetals.
Reference:
[1] Bioconjugate Chem. 2021, 32, 2257−2267
[2] Chem. Sci. 2019, 10, 4048−4053
[3] Front. Pharmacol 2022, 13, 764540
[4] PLoS ONE 11(6): e0157193
[5] Mol. Cancer Ther. 2023, 22, 999−1012
[6] J. Med. Chem. 2024, 67, 18124−18138