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. 2023 Feb 9;59(13):1841-1844.
doi: 10.1039/d2cc06677g.

Peroxide-cleavable linkers for antibody-drug conjugates

Nicola Ashman  1 , Jonathan D Bargh  1 , Stephen J Walsh  1   2 , Ryan D Greenwood  3 , Arnaud Tiberghien  4 , Jason S Carroll  2 , David R Spring  1
Affiliations

Peroxide-cleavable linkers for antibody-drug conjugates

Nicola Ashman et al. Chem Commun (Camb). .

Abstract

Antibody-drug conjugates containing peroxide-cleavable arylboronic acid linkers are described, which target the high levels of reactive oxygen species (ROS) in cancer. The arylboronic acid linkers rapidly release a payload in the presence of hydrogen peroxide, but remain stable in plasma. Anti-HER2 and PD-L1 peroxide-cleavable ADCs exhibited potent cytotoxicity in vitro.

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Conflict of interest statement

J. D. B. is now an employee of AstraZeneca. S. J. W. and A. T. are now employed by Bicycle Therapeutics.

Figures

Fig. 1
Fig. 1. Illustration of the “turn-on” fluorescence from model linkers and general oxidation of boronic acids by H2O2 (top), (a) kinetics of AMC release from peroxide-cleavable 1c and non-cleavable 2c model linkers, (b) AMC release is prevented when co-incubated with catalase, (c) model linkers are stable in media (DMEM) in the absence of H2O2, (d) model linkers are stable in human and mouse plasma by HPLC.
Fig. 2
Fig. 2. Synthetic route towards peroxide-cleavable model linker 1c.
Fig. 3
Fig. 3. (a) Synthetic route towards DVP-linker-MMAE 1f; (b) bioconjugation conditions to final ADC 1 and ADC 4.
Fig. 4
Fig. 4. (a) In vitro cytotoxicity of ADC 1 in HER2+ and HER2− breast cancer cell lines; (b) ADC 1 becomes non-toxic to MCF7 cells when H2O2 is scavenged by catalase (CAT).
Fig. 5
Fig. 5. (a) In vitro cytotoxicity of Durvalumab ADCs 4–6 in PD-L1 + and PD-L1 – breast cancer cell lines; (b) ADC 4 becomes non-toxic to MCF7 and MDA-MB-231 cells when H2O2 is scavenged by catalase (CAT).
See this image and copyright information in PMC

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