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ANTIBODY DRUG CONJUGATES

ortho-Quinone drugs go pro

Nature Chemistry volume 14, pages 719–720 (2022)Cite this article

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Antibody-mediated delivery of therapeutics has been primarily limited to agents containing amine, alcohol or thiol functional groups. Now, an approach has been developed to create stable and bio-reversible prodrugs that mask ortho-quinones. Drug release requires both protease activation followed by acid-assisted elimination.

One of the biggest challenges with chemotherapy is the relative lack of discrimination between cancer and healthy tissue. One approach to improve the selectivity is to use cancer cell-targeting antibodies that deliver a chemotherapeutic to the tumour while sparing other tissues from exposure to the drug. These antibody–drug conjugates or ADCs are highly complex and are based on the covalent attachment of a small-molecule cytotoxic drug to an antibody1. The method of attachment needs to be stable during circulation in the blood, but also able to release the drug after binding and internalization in the target cancer cell. After more than 40 years of research and development in this area, there are now eleven ADCs approved for human use, with seven of those approved in the past three years. Although these successful ADCs span a variety of cancer types, including both solid and hematologic tumours, they are all still limited by narrow therapeutic indices (the ratio between efficacious and toxic doses) — preventing even better patient outcomes and often precluding use in earlier lines of treatment.

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Fig. 1: ADC assembled with an ortho-quinone anti-cancer chemotherapeutic.

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  1. Genentech, South San Francisco, CA, USA

    Thomas Pillow

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  1. Thomas Pillow
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Correspondence to Thomas Pillow.

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Pillow, T. ortho-Quinone drugs go pro. Nat. Chem. 14, 719–720 (2022). https://doi.org/10.1038/s41557-022-00993-2

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