Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

ANTIBODY DRUG CONJUGATES

ortho-Quinone drugs go pro

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

Subjects

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.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

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

References

  1. Drago, J. Z., Modi, S. & Chandarlapaty, S. Nat. Rev. Clin. Oncol. 18, 327–344 (2021).

    Article  Google Scholar 

  2. Staben, L. R. et al. Nat. Chem. 8, 1112–1119 (2016).

    CAS  Article  Google Scholar 

  3. Kolakowski, R. V. et al. Angew. Chem. Int. Ed. 55, 7948–7951 (2016).

    CAS  Article  Google Scholar 

  4. Dunsmore, L. et al. Nat. Chem. https://doi.org/10.1038/s41557-022-00964-7 (2022).

    Article  PubMed  Google Scholar 

  5. Chuprakov, S. et al. Bioconjug. Chem. 32, 746–754 (2021).

    CAS  Article  Google Scholar 

  6. Gong, Q., Hu, J., Wang, P., Li, X. & Zhang, X. Eur. J. Med. Chem. 210, 112962 (2020).

    Article  Google Scholar 

  7. Ma, X. et al. J. Control. Release 200, 201–211 (2015).

    CAS  Article  Google Scholar 

  8. Lehar, S. M. et al. Nature 527, 323–328 (2015).

    CAS  Article  Google Scholar 

  9. Gadd, A. J. R., Greco, F., Cobb, A. J. A. & Edwards, A. D. Bioconjug. Chem. 26, 1743–1752 (2015).

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Genentech, South San Francisco, CA, USA

    Thomas Pillow

Authors
  1. Thomas Pillow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Pillow.

Ethics declarations

Competing interests

The author declares no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-022-00993-2

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing