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Hello, and welcome!

This post kicks off the second topic in the Exploring Precision Cancer Therapies series: Antibody-Drug Conjugates (ADCs). In this first post on ADCs, we’ll cover what they are, along with their general structure and mechanism of action. So, let’s jump in.

Contents

  1. What are ADCs?
  2. Basic Structure of ADCs
  3. How ADCs Work
  4. Closing Thoughts
  5. Acknowledgements/Disclosures
  6. References

What are ADCs?

ADCs are precion cancer therapy that utilizes antibody-antigen based targeting to selectively deliver cancer therapeutics to tumor cells [1, 2, 3]. As of late 2023 [4], there were 14 FDA-approved ADCs for the treatment of various cancers, including lymphomas, leukemia, and breast cancer, among others.

Basic Structure of ADCs

Antibody-drug conjugates (ADCs) have three key components [1, 2, 3]: a monoclonal antibody (mAb), a cytotoxic drug known as the payload, and a linker molecule that is used to conjugate the antibody and drug payload.

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The mAb provides the targeting functionality through binding to a tumor-specific target antigen [3, 5], allowing the drug payload to be delivered explicitly to target cancer cells with minimal off-target effects.

Although the schematic above depicts a single payload molecule, ADCs typically carry a payload of multiple drug molecules, referred to as the drug-antibody ratio (DAR), which may range from two to eight molecules [6]. It’s also possible to design dual payload ADCs that can deliver two different drugs for ADC-based combination therapy [7, 8].

There are two classes of linker molecules used in ADCs [3, 9]: cleavable and non-cleavable. The choice of linker affects ADC properties like circulation stability and drug release mechanism at the tumor site [5, 9]. Cleavable linkers are cleaved at a specific location in the tumor region by one of three main mechanisms [9, 10]: i) cleavage of peptide sequences by lysosomal proteases, ii) hydrolosis of an acid-sensitive chemical bond under the acidic pH of endosomes or lysosomes, or iii) disulfide bond reduction and cleavage driven by elevated levels of glutathione (GSH) in the cellular cytosol. On the other hand, non-cleavable linkers aren’t sensitive to such conditions and require complete lysosomal degradation of the ADC antibody for payload release [9, 10].

How ADCs Work

The first step of the ADC mechanism of action is selective binding to a particular antigen expressed (or overexpressed) by the cancer cells [3, 5, 11].

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The antigen targeting allows selective accumulation at the tumor site, which is followed by cellular uptake of ADC by endocytic mechanisms [12, 3, 11].

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Depending on the type of linker, the ADC then undergoes either cleavage or lysosomal degradation that ultimately results in the release of the drug payload [12, 3, 11]. After the payload has been released it can then go on to exert its cytotoxic effect to drive selective death of the targeted tumor cells.

Closing Thoughts

In this post, we covered some basics of antibody-drug conjugates (ADCs), including what they are, their basic structure, and their mechanism of action. This exciting approach to precision cancer therapy remains locked and loaded, taking advantage of antibody-antigen targeting to deliver its deadly payload to tumor cells. In the upcoming ADC Part II post, we’ll discuss an interesting phenomenon related to off-target effects associated with some ADCs called the bystander effect. We’ll also implement some semi-mechanistic PK/PD models for exploratory modeling and analysis of ADCs and the bystander effect.

That’s it for now. Feel free to message me if you have any questions or want to discuss something from this (or other) posts. I’m always open to feedback and suggestions, so if there is something you think I should cover or expand on in a future post, let me know! You can contact me through LinkedIn.

Lastly, please share this post with anyone else who might be interested. It is a massive help to me, as it increases the blog’s visibility and can help more people discover my work. And, stay tuned for Part II on ADCs!

Thanks for reading, and have a nice day! Until next time – Blake

Acknowledgements & Disclosures

Grammarly was used for proofreading and editing. Copilot was used to generate and initial outline of this post.

Schematics were created using Inkscape and GIMP GIMP.

References

  1. What is an Antibody-Drug Conjugate? | Sigma Aldrich.. (n.d.). Retrieved November 14, 2024, from https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/pharmaceutical-and-biopharmaceutical-manufacturing/antibody-drug-conjugate-manufacturing/antibody-drug-conjugate-overview?srsltid=AfmBOorSCvIa1ZNm1KeFNut30walrpe3swiX0AZ0YfmsKlhSc8N-Ranm
  2. Baah, S., Laws, M., & Rahman, K. M. (2021). Antibody–Drug Conjugates—A Tutorial Review. Molecules 2021, Vol. 26, Page 2943, 26(10), 2943. https://doi.org/10.3390/MOLECULES26102943
  3. FDA Approved Antibody-Drug Conjugates (ADCs) By 2024 | Biopharma PEG. (2019, October 30). https://www.biochempeg.com/article/74.html
  4. Shen, L., Sun, X., Chen, Z., Guo, Y., Shen, Z., Song, Y., Xin, W., Ding, H., Ma, X., Xu, W., Zhou, W., Che, J., Tan, L., Chen, L., Chen, S., Dong, X., Fang, L., & Zhu, F. (2024). ADCdb: the database of antibody–drug conjugates. Nucleic Acids Research, 52(D1), D1097–D1109. https://doi.org/10.1093/NAR/GKAD831
  5. Dean, A., & Zhang, B. (2021, May 26). Recent Advances in the Antibody-Drug Conjugate Clinical Pipeline | FDA. 2021 FDA Science Forum. https://www.fda.gov/science-research/fda-science-forum/recent-advances-antibody-drug-conjugate-clinical-pipeline
  6. Rosner, S., Valdivia, A., Hoe, H. J., Murray, J. C., Levy, B., Felip, E., & Solomon, B. J. (2023). Antibody-Drug Conjugates for Lung Cancer: Payloads and Progress. American Society of Clinical Oncology Educational Book, 43. https://doi.org/10.1200/
  7. Yamazaki, C. M., Yamaguchi, A., Anami, Y., Xiong, W., Otani, Y., Lee, J., Ueno, N. T., Zhang, N., An, Z., & Tsuchikama, K. (2021). Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance. Nature Communications 2021 12:1, 12(1), 1–13. https://doi.org/10.1038/s41467-021-23793-7
  8. Antibody-drug conjugates payloads: then, now and next. (n.d.). Retrieved November 14, 2024, from https://www.drugtargetreview.com/article/111783/antibody-drug-conjugates-payloads-then-now-and-next/
  9. What Are ADC Linkers: Cleavable vs. Non-Cleavable Linkers | Biopharma PEG. (2019, December 19). https://www.biochempeg.com/article/87.html
  10. Ponziani, S., di Vittorio, G., Pitari, G., Cimini, A. M., Ardini, M., Gentile, R., Iacobelli, S., Sala, G., Capone, E., Flavell, D. J., Ippoliti, R., & Giansanti, F. (2020). Antibody-Drug Conjugates: The New Frontier of Chemotherapy. International Journal of Molecular Sciences 2020, Vol. 21, Page 5510, 21(15), 5510. https://doi.org/10.3390/IJMS21155510
  11. The ABCs of ADCs: An Introduction to Antibody-drug Conjugates | iQ Biosciences. (n.d.). Retrieved November 14, 2024, from https://iqbiosciences.com/blog/the-abcs-of-adcs-an-introduction-to-antibody-drug-conjugates/

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