The Evolution of Antibody-Drug Conjugates (ADCs) in Cancer Therapy

Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potent cytotoxic effects of chemotherapeutic agents. The development of ADCs traces back over a century and mirrors advancements in molecular biology and biotechnology, resulting in several approved drugs used in oncology today. 

Early Beginnings: The Concept of Targeted Therapy 

The concept of targeted therapy in cancer treatment can be traced back to 1897 when Paul Ehrlich first proposed the idea of a "magic bullet," a drug that could selectively target pathogens without harming healthy cells. Ehrlich’s visionary concept laid the groundwork for ADC technology. However, it wasn’t until much later, with the advent of monoclonal antibodies (mAbs) and advances in biochemistry, that this idea would materialize into practical treatments for cancer. 

The first significant steps in ADC development occurred in the 1970s when researchers explored linking antibodies to chemotherapeutic agents. During this period, the hybridoma technique was developed by Milstein and Kohler, which allowed for the production of monoclonal antibodies with predefined specificity. This technology formed the foundation for the development of targeted therapies such as ADCs. 

The 1980s–1990s: Early Clinical Trials and Challenges 

Between the 1980s and 1990s, the first clinical trials involving ADCs for neoplastic diseases were conducted. However, these early trials faced significant setbacks. Toxicity and limited efficacy were the primary issues, as early ADCs struggled with problems like poor pharmacokinetics and high systemic toxicity. An example of this is the phase I trial of BR96-Doxorubicin, a chimeric anti-Lewis Y monoclonal antibody conjugated to doxorubicin. The trial targeted tumors expressing the Le(Y) antigen but ultimately yielded disappointing results due to severe toxicities. 

These challenges highlighted the limitations of early ADC designs, particularly the immunogenicity of murine antibodies and the instability of the linker technologies used to attach drugs to the antibody. During this period, researchers also began experimenting with highly cytotoxic payloads like calicheamicins, which offered the promise of more potent antitumor activity. 

2000: The First Approved ADC 

In 2000, a significant milestone in ADC development was reached with the FDA’s approval of gemtuzumab ozogamicin (GO), the first ADC to enter the market. GO was approved for the treatment of acute myeloid leukemia (AML) and marked the beginning of ADCs as viable therapeutic agents in oncology. GO used calicheamicin as its cytotoxic payload, linked to a humanized antibody targeting the CD33 antigen, a receptor commonly expressed on AML cells. 

However, GO’s journey was not without its own set of challenges. It was withdrawn from the market in 2010 due to safety concerns and disappointing clinical outcomes in post-approval studies. Despite these setbacks, GO was reintroduced in 2017 (US) and 2018 (EU) at a lower dose, with new administration protocols to mitigate toxicity. 

2011–2013: Breakthroughs in ADC Approvals 

Following the approval of GO, the next significant breakthrough in ADC development occurred in 2011 with the approval of brentuximab vedotin (BV) for Hodgkin lymphoma and systemic anaplastic large cell lymphoma (sALCL). Brentuximab vedotin was a marked improvement in ADC technology, using an anti-CD30 monoclonal antibody conjugated to the potent microtubule-disrupting agent monomethyl auristatin E (MMAE). This approval established ADCs as a crucial option in the treatment of hematologic malignancies. 

In 2013, the ADC field expanded into solid tumors with the approval of ado-trastuzumab emtansine (T-DM1), a breakthrough in breast cancer treatment. T-DM1 combined trastuzumab, a monoclonal antibody targeting HER2, with the cytotoxic agent DM1 (a derivative of maytansine). It represented the first ADC capable of selectively targeting HER2-positive solid tumors, further demonstrating the versatility of ADCs in oncology. 

2021: Expanding ADC Approvals 

By 2021, the FDA and EMA had approved 14 ADCs for the treatment of both solid tumors and hematologic cancers. The expansion of ADC approvals underscored the growing importance of these therapies in oncology. Among these, several key ADCs were recognized for their role in treating solid tumors, including: 

• Fam-trastuzumab deruxtecan (Enhertu): Approved for HER2-positive breast cancer, Enhertu leverages a higher drug–antibody ratio (DAR ~8) to improve the delivery of its cytotoxic payload, deruxtecan, to tumor cells. 

• Enfortumab vedotin (EV): Targeting Nectin-4, a protein overexpressed in urothelial carcinoma, enfortumab vedotin offers a new option for patients with advanced bladder cancer. 

• Sacituzumab govitecan (Trodelvy): Approved for triple-negative breast cancer (TNBC), this ADC utilizes an anti-TROP-2 antibody to deliver the topoisomerase I inhibitor SN-38 to tumor cells. 

Biointron’s catalog products for in vivo research can be found at Abinvivo, where we have a wide range of Antibody-Drug Conjugates, Bispecific Antibodies, Benchmark Positive Antibodies, Isotype Negative Antibodies, and Anti-Mouse Antibodies. Contact us to find out more at info@biointron.com or +86 400-828-8830 / +1(732)790-8340. 

References: 

1. Chis, A. A., Dobrea, C. M., Arseniu, A. M., Frum, A., Rus, L., Cormos, G., Georgescu, C., Morgovan, C., Butuca, A., Gligor, F. G., & Vonica-Tincu, A. L. (2024). Antibody–Drug Conjugates—Evolution and Perspectives. International Journal of Molecular Sciences, 25(13). https://doi.org/10.3390/ijms25136969